0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

The Effects of Seasons and Light Therapy on G Protein Levels in Mononuclear Leukocytes of Patients With Seasonal Affective Disorder FREE

Sofia Avissar, PhD; Gabriel Schreiber, MD, PhD; Yakov Nechamkin, MD; Isaac Neuhaus, BA; Gregory K. Lam, BS; Paul Schwartz, MD; Erick Turner, MD; Jeffery Matthews, MD; Susana Naim, MD; Norman E. Rosenthal, MD
[+] Author Affiliations

From the Departments of Clinical Pharmacology (Dr Avissar) and Psychiatry (Drs Schreiber and Nechamkin), Faculty for Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel (Drs Avissar, Schreiber, and Nechamkin); and Clinical Psychobiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Md (Messrs Neuhaus and Lam and Drs Schwartz, Turner, Matthews, Naim, and Rosenthal).


Arch Gen Psychiatry. 1999;56(2):178-183. doi:10.1001/archpsyc.56.2.178.
Text Size: A A A
Published online

Background  Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer.

Methods  Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gsα, Giα, and Gβ subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system.

Results  Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gsα and Giα proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects.

Conclusions  G protein–immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.

Figures in this Article

SEASONAL AFFECTIVE DISORDER (SAD) is a mood disorder characterized by recurrent episodes of winter depression, with remission or hypomanic periods in the spring and summer.1 Patients with SAD differ from patients with melancholia in their clinical profiles (SAD patients overeat, crave carbohydrates, gain weight, sleep more, and are tired frequently), as well as in their biological characteristics (eg, normal dexamethasone suppression test responses, normal responses to thyrotropin-releasing hormone challenge tests, and normal rapid eye movement sleep latency), which resemble those of patients with atypical depression.1 The efficacy of phototherapy for SAD has been generally acknowledged.2,3

Although there is no consensus on the pathophysiology of SAD or on the mechanism of action of light therapy, the mechanisms that have been suggested to account for these phenomena generally involve altered primary messenger function: abnormal brain serotonergic transmission,4 reduced sympathetic system arousal,5 and underactive hypothalamic-pituitary-adrenal axis functioning.6

The family of heterotrimeric G proteins is a crucial point of convergence in the transmission of signals from a variety of primary messengers and their membrane receptors to a series of downstream cellular events, including intracellular second messenger effector enzymes and ionic channels7,8 (Figure 1). The increasing interest in the clinical perspective of altered G protein function has yielded important findings concerning the involvement of G proteins in the pathophysiology of mood disorders and in the biochemical mechanisms underlying the treatment of these disorders. We found that the function of receptor-coupled G proteins was altered by treatment with lithium915 and other antibipolar medications.1315 Studies by other groups, generally in agreement with these results, implicate the involvement of G proteins in lithium's mechanism of action.1622 Increased G protein measures were detected in mononuclear leukocytes (MNLs) of patients with mania23,24 and in postmortem cerebral cortices of bipolar patients.2527 Reduced functional measures of G proteins were found in MNLs of patients with major depressive disorder.24,2830 Although conflicting results were obtained concerning G protein immunoreactive levels in MNLs of patients with major depression,31 a larger study has detected reduced levels of Gsα and Giα proteins in MNLs of depressed patients that correlated with the severity of depression and with reductions in the functional measures of these proteins.30 Quantitative and functional measures of G proteins in human MNLs were found to be age independent.32

Place holder to copy figure label and caption
Figure 1.

G protein as an information transducer from membrane receptor to intracellular effectors, the cycle of activation and inactivation. Heterotrimeric G proteins are located in the inner side of the cell membrane, playing a pivotal role in signal transduction beyond the receptor. The 3 G subunit proteins are α, β, γ. The α subunit contains the binding site for guanine nucleotides and possesses guanosine triphosphatase activity. The α subunit also contains the site for nicotinamide adenine nucleotide–dependent adenosine diphosphate–ribosylation catalyzed by cholera or pertussis bacterial toxins. The heterogeneity of α subunit serves to divide G proteins into the major classes (Gs, Gi, Go, Gq, etc). The β and γ subunits, which have their functional roles in signal transduction, form a tightly associated complex, which contributes to the receptor recognition site on the G protein oligomer and facilitates the attachment of the oligomer to the inner face of the plasma membrane. When a hormone or a neurotransmitter (H) binds to its specific receptor (R), it forms an activated receptor-G protein (G) complex. This induces guanine nucleotide exchange on the α subunit of G protein so that guanosine diphosphate (GDP) is displaced by guanosine triphosphate (GTP). The binding of GTP induces the dissociation of the G protein. The GTP-bound α subunit interacts with the effector (E) molecule (ie, adenylate cyclase or phospholipases) and affects its activity in producing respective second messengers (ie, cyclic adenosine monophosphate, inositol triphosphate, diacylglycerol). The GTP-bound α subunit has also intrinsic guanosine diphosphatase (GTPase) activity. The α subunit is then left in an inactive form tightly bound to GDP, and the G protein subunits reassociate. The rate-limiting step in this cycle is the release of GDP from the α subunit that is catalyzed through the activated receptor. Thus, G protein cycles between an inactive, GDP-liganded oligomeric form ("off" position), and an active, GTP-liganded monomeric state ("on" position).

Graphic Jump Location

This study attempts to characterize G protein levels in peripheral blood elements of patients with SAD by addressing the following questions: (1) Do reduced G protein levels, which are characteristic of MNLs of patients with nonseasonal, typical depression, also appear in patients with SAD, whose depressive symptoms are generally described as atypical? (2) Does light therapy, which is known to improve depressive symptoms in patients with SAD, normalize any alterations in MNL G protein levels detected in depressed patients with SAD? (3) Do any alterations in MNL G protein levels detected in depressed patients with SAD reflect trait or state characteristics? Toward this end, patients with SAD were followed up with measurement of MNL G protein levels while depressed during the winter months, following light therapy, and while in remission during the summer months.

SUBJECTS

Patients and controls were recruited through newspaper and radio advertisements in the Washington, DC, metropolitan area, by word of mouth, and through referrals from physicians, therapists, friends, or family. Twenty-six patients (18 women) met the following inclusion criteria: (1) Rosenthal et al1 diagnostic criteria for SAD, a pattern of recurrent depressions, at least 1 of which met criteria for a major depressive episode, and at least 2 of which occurred in consecutive years; (2) a score of at least 15 on the Structured Interview Guide for the Hamilton Depression Rating Scale–Seasonal Affective Disorders Version (SIGH-SAD33); (3) absence of any additional current Axis I disorders; (4) good physical health as determined by results of physical examination and routine blood work; and (5) no use of light therapy or medications for the current winter depression. The mean age of onset in cases where SAD could definitely be determined was 28 years. Thus, patients had SAD for an average of 13 years. Of the 26 patients, 17 (13 women) had unipolar and 9 (5 women) bipolar II characteristics. Twenty-eight healthy controls (20 women) were matched with patients on the basis of age, sex, body mass index (BMI or Quetelet index: calculated as weight in kilograms divided by the square of the height in meters),2 menstrual phase, and birth control status for women (4 women). Controls were required to have no personal or family history of Axis I psychiatric disorder and to be physically healthy. There were no significant differences (control vs SAD) in age (mean age, 46 years; range, 26-51 years vs mean age, 41 years; range, 26-60 years) and BMI (25.9±11.4 vs 26.4±11.2). Patients and healthy subjects were free of psychotropic medications for 1 month prior to the study, free of nonpsychotropic medications for 2 weeks prior to the study, and were allowed no more than 2 caffeinated beverages per day for 2 weeks prior to the study.

STUDY DESIGN

Subjects were studied during the winter (mean date, February 26, 1996±29 days vs mean date, February 26,1996±32 days) in an untreated condition. Nineteen of the 26 patients with SAD were studied again after 2 weeks of standard light therapy. Of the 7 patients who did not receive light therapy, 5 missed the appointment during which blood for the study was scheduled to be drawn. The other 2 patients had poor treatment compliance, so we did not include them (blood was not withdrawn a second time) because the data would have been misleading. The patients received light therapy (10,000 lux) from a light box, 60 cm × 60 cm (SunBox Co, Gaithersburg, Md). The distance from the center of patient's forehead to center of the box was 30.48 cm. Light therapy was administered at home for 45 minutes, twice per day, once between 6 and 9 AM, and once between 6 and 9 PM, as has previously been described by Terman et al.34 The summer group of the same patients included 22 patients, as 4 could not be reached. Remission was defined as not meeting criteria for major depression plus having SIGH-SAD scores of less than 10. Nonresponders were defined as meeting criteria for major depression plus having SIGH-SAD scores of more than 15. The same group of healthy volunteers was studied twice: during winter (28 subjects) and during summer (25 subjects; 2 could not be reached and 1 dropped out). Healthy volunteers did not receive light treatment in this study. Patients and healthy volunteers participated in the summer portion of the study between May 28 and July 25, 1996. For each study, 30 mL of blood was drawn in the morning (between 7 and 9 AM) at the Clinical Center of the National Institutes of Health, Bethesda, Md. The SIGH-SAD ratings were administered within 1 day of drawing the blood. Written informed consent was obtained after the procedures had been fully explained to the patients and the healthy subjects.

Several MNL preparations that were shipped from the United States to Israel could not be analyzed owing to technical problems in their preparations. These samples were either substantially contaminated with other cellular elements so that a sufficient quantity of MNL membrane protein could not be achieved in the MNL membrane preparations, or they were nonhomogeneous, forming large and/or dense cellular aggregates that could not be used for our assay. There was not enough MNL membrane protein for all G protein examinations in some subjects owing to the limited amount of blood that was drawn (30 mL), together with several preparations that resulted in a lower yield of MNLs in the Ficoll-Hypaque gradient (Pharmacia, Uppsala, Sweden). In these cases, MNL preparations were serially assigned only to part of the immunoreactive determinations of the G protein subunits. Thus, from 26 untreated patients with SAD and atypical winter depression, 21 were examined for Gsα and Giα immunoreactivities, and 22 for Gβ immunoreactivity. After 2 weeks of light therapy, 15 of the 19 patients were evaluated for Gsα, 16 for Giα, and 19 for Gβ. Of the 22 patients with SAD examined in the summer, 17 were analyzed for Gsα, 20 for Giα, and 20 for Gβ. In the winter group, 21 of 28 healthy volunteer subjects were assessed for Gsα, 17 for Giα, and 15 for Gβ immunoreactivities, while in the summer group of the same subjects, 19 of 25 were measured for Gsα and 18 for Giα and Gβ.

The study was approved by the institutional review board of the National Institutes of Mental Health. All the clinical work and MNL preparation was conducted in Bethesda. Frozen shipped MNL membranes were prepared and measured for G proteins in Israel. Experimenters in Israel who determined protein concentrations of the samples, ran the samples electrophoretically, and conducted immunoblotting and densitometry were blind to the diagnoses and/or state of the subjects. Gel protocols were prepared in advance to include matched controls in each gel.

MNL Isolation

Mononuclear leukocytes were isolated from 30 mL of heparinized fresh blood, using Ficoll-Hypaque gradient. Cells were homogenized in 25-mmol/L Tris-hydrochloride, pH 7.4, and 1-mmol/L dithiothreitol. The homogenate was passed through 2 layers of cheesecloth to remove debris, and membranes were collected by further centrifugation at 18,000g for 10 minutes. Membranes were then suspended in homogenization buffer containing 1-mmol/L ethyleneglycotetraacetic acid and 30% sucrose wt/vol and frozen at −70°C until assayed. Aliquots were taken for protein concentration determination using the Bradford assay.

Immunoblot Analysis

On the day of assay, membranes were thawed, aliquots of 10 µg taken for protein separation by 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis, and the resulting proteins transferred to nitrocellulose paper by use of an electroblotting apparatus. Blots were washed in Tris-buffered saline containing 3% polyoxyethelene-sorbitan monolaurate (TTBS), and blocked by incubation with 5% bovine serum albumin for 1 hour in Tris-buffered saline containing 0.1% polyoxyethelene-sorbitan monolaurate. After 2 washes in TTBS, blots were incubated overnight with each of the following antisera (Santa Cruz Biotechnology Inc, Santa Cruz, Calif) directed specifically against Gsα, Giα1,2, and Gβ (all diluted 1:100), followed by subsequent incubation with goat antirabbit IgG labeled with horseradish peroxidase (Jackson Immunoresearch Laboratories Inc, Westgrove, Pa). Immunoreactivity was detected with a Western blot detection system (Enhanced Chemiluminescence Western Blot Detection System; Amersham, Buckinghamshire, England) followed by exposure to film (Kodak X-Omat; Kodak, Rochester, NY).

Assay linearity ranged from 2.5 to 15 µg. Peak heights of immunoreactive bands were determined with an image analysis system and semiquantitative analysis was carried out. The optical density of the immunoreactive bands was normalized against 10-µg rat cortical membranes, run in each blot as a standard value. Although anti-Gsα detects both 52- and 45-kd Gsα species, only the 45-kd species is consistently detected in leukocytes, while rat cortex membranes predominantly show the 52-kd species. The other subunits assayed in leukocytes were found to migrate at the expected molecular weights similarly to those labeled in the rat cortex membranes.

Statistical Analysis

The Wilcoxon signed rank test was used for intrablot comparisons, which are singular matched comparisons within immunoblots, with an α level of significance of .05. For interblot average comparisons, the Mann-Whitney U test was used and was corrected for multiple comparisons by the Bonferroni adjustment, with α level of significance of .02.

There were no significant differences in G protein levels between winter and summer samples of the controls. Normalizing the winter samples as our comparison reference, the results show similar Gsα, Giα, and Gβ immunoreactivities for the control subjects during winter and summer: for Gsα, (100.0%±20.4%) vs (99.3%±18.3%), 2-tailed Wilcoxon statistic (W)=4, n=19, P>.05; for Giα, (100.0%±29.5%) vs (97.2%±28.4%), W=30, n=17, not significant; for Gβ: (100.0%±24.1%) vs (102%+22.2%), W=−12, n=15, not significant, Wilcoxon signed rank test).

Figure 2 shows that Gsα and Giα immunoreactive levels in MNLs of patients with winter depression (71.9%±22.4% and 79.5%±23.2%, respectively), were significantly reduced in comparison with the respective levels in healthy subjects (100.0%±15.8% and 100%+7.2%), using both intrablot matched comparisons (for Gsα: W=195, n=21, P<.01; for Giα: W=221, n=21,P<.01, Wilcoxon signed rank test) and interblot average comparisons (for Gsα: the Mann-Whitney test statistic [Us]=379, t40=3.99, P<.01; for Giα: Us=274,t36=2.8, P<.01, Mann-Whitney test). In contrast, MNL Gβ levels of depressed patients with SAD (100.6%±16.6%) were similar to levels in healthy volunteers (100.0%±9.4%), as calculated using both interblot average comparison (Us=170, t35=0.15, not significant, Mann-Whitney test), and intrablot matched comparisons (W=37, n=22, not significant, Wilcoxon signed rank test).

Place holder to copy figure label and caption
Figure 2.

The effect of light therapy on the immunoreactivity of various G protein subunits in the mononuclear leukocyte levels of patients with seasonal affective disorder. The relative immunoreactivities of Gsα (left panel), Giα (middle panel), and Gβ (right panel) determined in the mononuclear leukocytes were obtained from patients with seasonal affective disorder while depressed; 21 were examined for Gsα and Giα, and 22 for Gβ (open circles). After 2 weeks of light therapy, 15 were evaluated for Gsα, 16 for Giα, and 19 for Gβ (closed circles) as compared with normal subjects for which 21 were assessed for Gsα, 17 for Giα, and 15 for Gβ (open squares).

Graphic Jump Location

Two weeks of light therapy resulted in clinical remission in patients with SAD with decreases in typical, atypical, and total SIGH-SAD scores (Table 1). After 2 weeks of light therapy, the reduced Gsα and Giα levels in the depressed patients with SAD were significantly elevated to normal levels (for Gsα: 95.7%±24.2%, W=85, n=15, P<.02; for Giα: 103.4%±23.6%, W=90, n=16, P<.02; Wilcoxon signed rank test), while Gβ levels, (100.3%±14.3%) remained similar to the control values obtained for depressed patients with SAD (W=5, n=18, not significant, Wilcoxon signed rank test) (Figure 2). The table shows that Gsα and Giα protein normalization paralleled clinical remission in all treated patients as well as in the subgroups of responders and nonresponders.

Table Graphic Jump LocationComparison Between Clinical Improvement of Depressed Patients With SAD Treated With Light Therapy and the Normalization of G Protein Measures in Mononuclear Leukocytes of Patients*

During the summer, the SIGH-SAD scores show the patients with SAD to be in remission (Table 1), with levels of MNL Gsα (102.3%±19.5%), Giα (102.9%±21.7%), and Gβ (101.5%+18.7%) similar to levels obtained for healthy subjects (for Gsα: Us=169,t34=0.24, not significant; for Giα: Us=218, t36=1.11, not significant; for Us=170, t36=0.25, Mann-Whitney test).

A major finding of this study is the description of reduced levels of Gsα and Giα subunit proteins in MNLs of patients with SAD winter, atypical-type depression. These findings are compatible with previous studies in patients with typical major depression.24,2830 The G protein abnormalities detected in this study in depressed patients with SAD seem to be a state rather than a trait marker of SAD since (1) the same patients examined for their MNL G proteins levels in the summer, while in remission, did not show statistically significant alterations when compared with healthy control subjects; and (2) light therapy resulted in normalization of the reduced G protein immunoreactivity detected in the same patients while depressed. The results of this study are consistent with our earlier reports of MNL G protein measures as a state characteristic of mood disorders: (1) inverse picture of MNL G protein measures in bipolar mood disorder with respective increases in mania and decreases in bipolar depression23,24,28,30; and (2) normalization of MNL G protein measures in patients with mood disorders with lithium,23 antidepressants, and electroconvulsive therapy.35

The mechanisms underlying the alterations in G protein levels in MNL of depressed patients with SAD and their normalization by light are still unknown. Increasing evidence indicates the existence of neural-mediated immunomodulatory mechanisms36 involving the hypothalamic-pituitary-adrenal axis and the sympathetic and parasympathetic innervation of primary and secondary lymphoid organs.37 These mechanisms may modulate MNL G proteins. Thus, MNL G protein alterations may reflect secondary influences of circulatory primary messengers, altered by the depressive state, or secondary influences of altered sympathetic and parasympathetic innervation of lymphoid organs induced by the depressive state.

We are aware that the involvement of G proteins in the pathophysiology of depression as implicated from the data presented here should be taken with considerable caution: findings obtained in peripheral blood cells cannot be directly extrapolated to the central nervous system. We have discussed this issue at length previously.30 As we use a mixed-cell MNL preparation for our assays, the possibility remains that the alterations observed in G protein immunoreactivity reflect, at least in part, alteration in a white cell subpopulation induced by the depressive state and/or by light therapy. While Gsα and Giα levels were reduced in the group of depressed patients with SAD, the Gβ levels remained similar to the control group. Such differential alterations would not be expected to occur owing to alterations in a white cell subpopulation.

If changes observed in MNL G protein levels in this study do reflect alterations in brain G proteins, a possible candidate may be transducin (Gt protein), which connects rhodopsin with a retinal phosphodiesterase regulating cyclic guanosine monophosphate, sodium permeability of the rod outer segment membrane, and, consequently, the electroretinogram (ERG).38 It has been shown that lithium can decrease ERG amplitude and that these effects are related to inhibition of transducin,16 similar to the inhibition of Gs and Gi proteins reported previously.9,10 Indeed, ERG measurements have been conducted in SAD, indicating either subtle retinal changes in flash ERG39 or no changes in pattern ERG40 in depressed patients with SAD. The findings in this study of reduced MNL G protein levels in depressed patients with SAD may explain the reported subsensitivity to light in depressed patients with SAD41,42 by conjecturing reduced levels of transducin (Gt). Light treatment found in this study to normalize the reduced levels of MNL G proteins in depressed patients with SAD may exert its effects centrally through possible normalization of supposed Gt protein hypofunction.

Another state marker of depressed patients with SAD is their abnormal response to the somewhat selective 5-hydroxytryptamine2C agonist meta-chlorophenylpiperazine.43,44 The reported activation and euphoria seen in depressed patients with SAD, but not in healthy controls, following administration of meta-chlorophenylpiperazine is normalized both after effective light therapy44,45 and in the summer.43 In this regard, the meta-chlorophenylpiperazine findings resemble those in this study. Most 5-hydroxytryptamine receptor subtypes are G protein–coupled, including 5-hydroxytryptamine2C. It is possible that both light therapy and summer, which reverse the depressive symptoms of SAD, may also normalize G protein levels in both the brain and the periphery. Such putative normalization may be of relevance to the pathogenesis of symptoms.

Accepted for publication November 18, 1998.

This study was supported by a research grant from the Chief Scientist Office of the Israel Ministry of Health, Jerusalem (Drs Schreiber and Avissar), by the Yadgarov Family Foundation, Tel-Aviv, Israel (Dr Schreiber), and by the Intramural Program of the National Institute of Mental Health, National Institutes of Health, Bethesda, Md.

Corresponding author: Sofia Avissar, PhD, Department of Clinical Pharmacology, Ben Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel (e-mail: sofia@bgumail.bgu.ac.il).

Rosenthal  NESack  DAGillin  JCLewy  A JGoodwin  FKDavenport  YMueller  PSWehr  TA Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry. 1984;4172- 80
Link to Article
Rosenthal  NE Diagnosis and treatment of seasonal affective disorder. J Am Med Assoc. 1993;2702717- 2720
Link to Article
Task Force Report of the American Psychiatric Association, Treatment of Psychiatric Disorders. Vol 3 Boston, Mass APA Press1989;31890- 1896
Rosenthal  NE The Mechanism of Action of Light in the Treatment of Seasonal Affective Disorder (SAD) in Biologic Effects of Light.  Berlin, Germany Walter de Gruyter & Co1996;311- 324
Rudorfer  MVSkwerer  RGRosenthal  NE Biogenic amines in seasonal affective disorder: effects of light therapy. Psychiatry Res. 1993;4619- 28
Link to Article
Joseph-Vanderpool  JRRosenthal  NEChrousos  GWehr  TAKasper  SGold  PW Abnormal pituitary-adrenal responses to CRH in patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab. 1991;721382- 1387
Link to Article
Gilman  AG G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56615- 649
Link to Article
Hepler  JRGilman  AG G proteins. Trends Biochem Sci. 1992;17383- 387
Link to Article
Avissar  SSchreiber  GDanon  ABelmaker  RH Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature. 1988;331440- 442
Link to Article
Avissar  SSchreiber  G Muscarinic receptor subclassification and G proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics [Bennett Award Paper]. Biol Psychiatry. 1989;26113- 130
Link to Article
Avissar  SMurphy  DLSchreiber  G Magnesium reverses lithium inhibition of beta adrenergic and muscarinic receptor coupling to G proteins. Biochem Pharmacol. 1991;41171- 175
Link to Article
Schreiber  GAvissar  SAulakh  CSMurphy  DL Lithium-selective alteration of brain vs cardiac Gs protein function. Neuropharmacology. 1990;291067- 1071
Link to Article
Avissar  SSchreiber  GAulakh  CSMurphy  DL Carbamazepine and electroconvulsive shock attenuate beta-adrenoceptor and muscarinic cholinoceptor coupling to G proteins in rat cortex. Eur J Pharmacol. 1990;10099- 103
Link to Article
Avissar  SSchreiber  G The involvement of G proteins in the pathogenesis and treatment of affective disorders. Biol Psychiatry. 1992;31435- 459
Link to Article
Avissar  SSchreiber  G Interaction of antibipolar and antidepressant treatments with receptor-coupled G proteins. Pharmacopsychiatry. 1992;2544- 50
Link to Article
Meyniel  GDoly  MGallard  G Electrophysiological demonstration of transducin inhibition by lithium. C R Acad Sci III. 1989;309289- 294
Mork  AGeisler  A Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum and hippocampus from rats treated chronically with lithium. Biol Psychiatry. 1989;26279- 288
Link to Article
Newman  MEShapira  BLerer  B Effects of lithium and desipramine on second messenger responses in rat hippocampus: relation to G protein effects. Neuropharmacology. 1991;301297- 13101
Link to Article
Manji  HKBitran  JMasana  MChen  GHsiao  JKRisby  EDRudorfer  MWPotter  WZ Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies. Psychopharmacol Bull. 1991;27199- 208
Song  LJope  RS Chronic lithium treatment impairs phosphatidylinositol hydrolysis in membranes from rat brain regions. J Neurochem. 1992;582200- 2206
Link to Article
Li  PPTam  YKYoung  LTWarsh  JJ Lithium decreases Gs, Gi-1, Gi-2 α subunit mRNA levels in rat cortex. Eur J Pharmacol. 1991;206165- 166
Link to Article
Lesch  KPAulakh  CSTolliver  TJHill  JLWolozin  BLMurphy  DL Differential effects of long-term lithium and carbamazepine administration on Gsα and Giα protein in rat brain. Eur J Pharmacol. 1991;207355- 359
Link to Article
Schreiber  GAvissar  SDanon  ABelmaker  RH Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry. 1991;29273- 280
Link to Article
Avissar  SNechamkin  YRoitman  GSchreiber  G Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord. 1997;4385- 93
Link to Article
Friedman  EWang  HY Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem. 1996;671145- 1152
Link to Article
Young  LTLi  PPKish  SJSiu  KPWarsh  JJ Post mortem cerebral cortex Gsα subunit levels are elevated in bipolar affective disorder. Brain Res. 1991;553323- 326
Link to Article
Young  LTLi  PPKish  SJSiu  KPKamble  AHornykiewics  OWarsh  JJ Cerebral cortex Gs protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem. 1993;61890- 898
Link to Article
Avissar  SBarki-Harrington  LNechamkin  YRoitman  GSchreiber  G Reduced β-adrenergic receptor-coupled Gs protein function and Gsα immunoreactivity in mononuclear leukocytes of patients with depression. Biol Psychiatry. 1996;39755- 760
Link to Article
Karege  FBovier  PStepanian  RGaillard  JM Change in platelet GTP-binding protein in drug-free depressed patients. Hum Psychopharmacol. 1996;11115- 121
Link to Article
Avissar  SNechamkin  YRoitman  GSchreiber  G Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression. Am J Psychiatry. 1997;154211- 217
Young  LTLi  PPKamble  ASiu  KPWarsh  JJ Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry. 1994;151594- 596
Barki-Harrington  LNechamkin  YSchreiber  GAvissar  S Functional and quantitative measures of receptor coupled G proteins in human mononuclear leukocytes: no change with age. Exp Gerontol. 1996;31351- 363
Link to Article
Williams  JBWLink  MJRosenthal  NETerman  M Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective Disorder Version.  New York, NY New York State Psychiatric Institute1988;
Terman  JSTerman  MSchlager  DRaftery  BRosofsky  ABLink  MJGallin  PFQuitkin  FM Efficacy of brief, intense light exposure for treatment of winter depression. Psychopharmacol Bull. 1990;263- 11
Avissar  SNechamkin  YRoitman  GSchreiber  G Normalization dynamics by electroconvulsive treatment of reduced G protein levels and functions in mononuclear leukocytes of patients with major depression. Am J Psychiatry. 1998;155666- 671
Roszman  TLBrooks  WH Neural modulation of immune function. J Neuroimmunol. 1985;1059- 69
Link to Article
Livnat  SFelten  SYCarlson  SLBellinger  DLFelten  DL Involvement of peripheral and central catecholamine systems in neural immune interactions. J Neuroimmunol. 1985;105- 30
Link to Article
Fung  BKKHurley  JBStryer  L Flow of information in the light-triggered cyclic nucleotide cascade of vision. Proc Natl Acad Sci USA. 1981;78152- 156
Link to Article
Lam  RWBeattie  CWBuchanan  AMador  JA Electroretinography in seasonal affective disorder. Psychiatry Res. 1992;4355- 63
Link to Article
Oren  DAMoul  DESchwartz  PJAlexander  JRYamada  EMRosenthal  NE An investigation of ophthalmic function in winter seasonal affective disorder. Depression. 1993;129- 37
Link to Article
Lam  RWBeattie  CWBuchanan  ARemick  RAZis  AP Low electrooculographic ratios in patients with seasonal affective disorder. Am J Psychiatry. 1991;1481526- 1529
Ozaki  NRosenthal  NEMyers  FSchwartz  PJOren  DA Effects of season on electro-oculographic ratio in winter seasonal affective disorder. Psychiatry Res. 1995;59151- 155
Link to Article
Joseph-Vanderpool  JRJacobsen  FMMurphy  DLHill  JLRosenthal  NE Seasonal variation in behavioral responses to m-CPP in patients with seasonal affective disorder and controls. Biol Psychiatry. 1993;33496- 504
Link to Article
Schwartz  PJMurphy  DLGarcia-Borreguero  DOren  DAMoul  DEOzaki  NSnelbaker  AJWehr  TARosenthal  NE Effects of m-CPP infusions in patients with seasonal affective disorder and healthy controls: diurnal responses and nocturnal regulatory mechanisms. Arch Gen Psychiatry. In press.
Jacobsen  FMMueller  EARosenthal  NERogers  SHill  JLMurphy  DL Behavioral responses to intravenous meta-chlorophenylpiperazine in patients with seasonal affective disorder and control subjects before and after phototherapy. Psychiatry Res. 1994;52181- 197
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

G protein as an information transducer from membrane receptor to intracellular effectors, the cycle of activation and inactivation. Heterotrimeric G proteins are located in the inner side of the cell membrane, playing a pivotal role in signal transduction beyond the receptor. The 3 G subunit proteins are α, β, γ. The α subunit contains the binding site for guanine nucleotides and possesses guanosine triphosphatase activity. The α subunit also contains the site for nicotinamide adenine nucleotide–dependent adenosine diphosphate–ribosylation catalyzed by cholera or pertussis bacterial toxins. The heterogeneity of α subunit serves to divide G proteins into the major classes (Gs, Gi, Go, Gq, etc). The β and γ subunits, which have their functional roles in signal transduction, form a tightly associated complex, which contributes to the receptor recognition site on the G protein oligomer and facilitates the attachment of the oligomer to the inner face of the plasma membrane. When a hormone or a neurotransmitter (H) binds to its specific receptor (R), it forms an activated receptor-G protein (G) complex. This induces guanine nucleotide exchange on the α subunit of G protein so that guanosine diphosphate (GDP) is displaced by guanosine triphosphate (GTP). The binding of GTP induces the dissociation of the G protein. The GTP-bound α subunit interacts with the effector (E) molecule (ie, adenylate cyclase or phospholipases) and affects its activity in producing respective second messengers (ie, cyclic adenosine monophosphate, inositol triphosphate, diacylglycerol). The GTP-bound α subunit has also intrinsic guanosine diphosphatase (GTPase) activity. The α subunit is then left in an inactive form tightly bound to GDP, and the G protein subunits reassociate. The rate-limiting step in this cycle is the release of GDP from the α subunit that is catalyzed through the activated receptor. Thus, G protein cycles between an inactive, GDP-liganded oligomeric form ("off" position), and an active, GTP-liganded monomeric state ("on" position).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The effect of light therapy on the immunoreactivity of various G protein subunits in the mononuclear leukocyte levels of patients with seasonal affective disorder. The relative immunoreactivities of Gsα (left panel), Giα (middle panel), and Gβ (right panel) determined in the mononuclear leukocytes were obtained from patients with seasonal affective disorder while depressed; 21 were examined for Gsα and Giα, and 22 for Gβ (open circles). After 2 weeks of light therapy, 15 were evaluated for Gsα, 16 for Giα, and 19 for Gβ (closed circles) as compared with normal subjects for which 21 were assessed for Gsα, 17 for Giα, and 15 for Gβ (open squares).

Graphic Jump Location

Tables

Table Graphic Jump LocationComparison Between Clinical Improvement of Depressed Patients With SAD Treated With Light Therapy and the Normalization of G Protein Measures in Mononuclear Leukocytes of Patients*

References

Rosenthal  NESack  DAGillin  JCLewy  A JGoodwin  FKDavenport  YMueller  PSWehr  TA Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry. 1984;4172- 80
Link to Article
Rosenthal  NE Diagnosis and treatment of seasonal affective disorder. J Am Med Assoc. 1993;2702717- 2720
Link to Article
Task Force Report of the American Psychiatric Association, Treatment of Psychiatric Disorders. Vol 3 Boston, Mass APA Press1989;31890- 1896
Rosenthal  NE The Mechanism of Action of Light in the Treatment of Seasonal Affective Disorder (SAD) in Biologic Effects of Light.  Berlin, Germany Walter de Gruyter & Co1996;311- 324
Rudorfer  MVSkwerer  RGRosenthal  NE Biogenic amines in seasonal affective disorder: effects of light therapy. Psychiatry Res. 1993;4619- 28
Link to Article
Joseph-Vanderpool  JRRosenthal  NEChrousos  GWehr  TAKasper  SGold  PW Abnormal pituitary-adrenal responses to CRH in patients with seasonal affective disorder: clinical and pathophysiological implications. J Clin Endocrinol Metab. 1991;721382- 1387
Link to Article
Gilman  AG G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56615- 649
Link to Article
Hepler  JRGilman  AG G proteins. Trends Biochem Sci. 1992;17383- 387
Link to Article
Avissar  SSchreiber  GDanon  ABelmaker  RH Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature. 1988;331440- 442
Link to Article
Avissar  SSchreiber  G Muscarinic receptor subclassification and G proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics [Bennett Award Paper]. Biol Psychiatry. 1989;26113- 130
Link to Article
Avissar  SMurphy  DLSchreiber  G Magnesium reverses lithium inhibition of beta adrenergic and muscarinic receptor coupling to G proteins. Biochem Pharmacol. 1991;41171- 175
Link to Article
Schreiber  GAvissar  SAulakh  CSMurphy  DL Lithium-selective alteration of brain vs cardiac Gs protein function. Neuropharmacology. 1990;291067- 1071
Link to Article
Avissar  SSchreiber  GAulakh  CSMurphy  DL Carbamazepine and electroconvulsive shock attenuate beta-adrenoceptor and muscarinic cholinoceptor coupling to G proteins in rat cortex. Eur J Pharmacol. 1990;10099- 103
Link to Article
Avissar  SSchreiber  G The involvement of G proteins in the pathogenesis and treatment of affective disorders. Biol Psychiatry. 1992;31435- 459
Link to Article
Avissar  SSchreiber  G Interaction of antibipolar and antidepressant treatments with receptor-coupled G proteins. Pharmacopsychiatry. 1992;2544- 50
Link to Article
Meyniel  GDoly  MGallard  G Electrophysiological demonstration of transducin inhibition by lithium. C R Acad Sci III. 1989;309289- 294
Mork  AGeisler  A Effects of GTP on hormone-stimulated adenylate cyclase activity in cerebral cortex, striatum and hippocampus from rats treated chronically with lithium. Biol Psychiatry. 1989;26279- 288
Link to Article
Newman  MEShapira  BLerer  B Effects of lithium and desipramine on second messenger responses in rat hippocampus: relation to G protein effects. Neuropharmacology. 1991;301297- 13101
Link to Article
Manji  HKBitran  JMasana  MChen  GHsiao  JKRisby  EDRudorfer  MWPotter  WZ Signal transduction modulation by lithium: cell culture, cerebral microdialysis and human studies. Psychopharmacol Bull. 1991;27199- 208
Song  LJope  RS Chronic lithium treatment impairs phosphatidylinositol hydrolysis in membranes from rat brain regions. J Neurochem. 1992;582200- 2206
Link to Article
Li  PPTam  YKYoung  LTWarsh  JJ Lithium decreases Gs, Gi-1, Gi-2 α subunit mRNA levels in rat cortex. Eur J Pharmacol. 1991;206165- 166
Link to Article
Lesch  KPAulakh  CSTolliver  TJHill  JLWolozin  BLMurphy  DL Differential effects of long-term lithium and carbamazepine administration on Gsα and Giα protein in rat brain. Eur J Pharmacol. 1991;207355- 359
Link to Article
Schreiber  GAvissar  SDanon  ABelmaker  RH Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry. 1991;29273- 280
Link to Article
Avissar  SNechamkin  YRoitman  GSchreiber  G Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord. 1997;4385- 93
Link to Article
Friedman  EWang  HY Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem. 1996;671145- 1152
Link to Article
Young  LTLi  PPKish  SJSiu  KPWarsh  JJ Post mortem cerebral cortex Gsα subunit levels are elevated in bipolar affective disorder. Brain Res. 1991;553323- 326
Link to Article
Young  LTLi  PPKish  SJSiu  KPKamble  AHornykiewics  OWarsh  JJ Cerebral cortex Gs protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. J Neurochem. 1993;61890- 898
Link to Article
Avissar  SBarki-Harrington  LNechamkin  YRoitman  GSchreiber  G Reduced β-adrenergic receptor-coupled Gs protein function and Gsα immunoreactivity in mononuclear leukocytes of patients with depression. Biol Psychiatry. 1996;39755- 760
Link to Article
Karege  FBovier  PStepanian  RGaillard  JM Change in platelet GTP-binding protein in drug-free depressed patients. Hum Psychopharmacol. 1996;11115- 121
Link to Article
Avissar  SNechamkin  YRoitman  GSchreiber  G Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression. Am J Psychiatry. 1997;154211- 217
Young  LTLi  PPKamble  ASiu  KPWarsh  JJ Mononuclear leukocyte levels of G proteins in depressed patients with bipolar disorder or major depressive disorder. Am J Psychiatry. 1994;151594- 596
Barki-Harrington  LNechamkin  YSchreiber  GAvissar  S Functional and quantitative measures of receptor coupled G proteins in human mononuclear leukocytes: no change with age. Exp Gerontol. 1996;31351- 363
Link to Article
Williams  JBWLink  MJRosenthal  NETerman  M Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective Disorder Version.  New York, NY New York State Psychiatric Institute1988;
Terman  JSTerman  MSchlager  DRaftery  BRosofsky  ABLink  MJGallin  PFQuitkin  FM Efficacy of brief, intense light exposure for treatment of winter depression. Psychopharmacol Bull. 1990;263- 11
Avissar  SNechamkin  YRoitman  GSchreiber  G Normalization dynamics by electroconvulsive treatment of reduced G protein levels and functions in mononuclear leukocytes of patients with major depression. Am J Psychiatry. 1998;155666- 671
Roszman  TLBrooks  WH Neural modulation of immune function. J Neuroimmunol. 1985;1059- 69
Link to Article
Livnat  SFelten  SYCarlson  SLBellinger  DLFelten  DL Involvement of peripheral and central catecholamine systems in neural immune interactions. J Neuroimmunol. 1985;105- 30
Link to Article
Fung  BKKHurley  JBStryer  L Flow of information in the light-triggered cyclic nucleotide cascade of vision. Proc Natl Acad Sci USA. 1981;78152- 156
Link to Article
Lam  RWBeattie  CWBuchanan  AMador  JA Electroretinography in seasonal affective disorder. Psychiatry Res. 1992;4355- 63
Link to Article
Oren  DAMoul  DESchwartz  PJAlexander  JRYamada  EMRosenthal  NE An investigation of ophthalmic function in winter seasonal affective disorder. Depression. 1993;129- 37
Link to Article
Lam  RWBeattie  CWBuchanan  ARemick  RAZis  AP Low electrooculographic ratios in patients with seasonal affective disorder. Am J Psychiatry. 1991;1481526- 1529
Ozaki  NRosenthal  NEMyers  FSchwartz  PJOren  DA Effects of season on electro-oculographic ratio in winter seasonal affective disorder. Psychiatry Res. 1995;59151- 155
Link to Article
Joseph-Vanderpool  JRJacobsen  FMMurphy  DLHill  JLRosenthal  NE Seasonal variation in behavioral responses to m-CPP in patients with seasonal affective disorder and controls. Biol Psychiatry. 1993;33496- 504
Link to Article
Schwartz  PJMurphy  DLGarcia-Borreguero  DOren  DAMoul  DEOzaki  NSnelbaker  AJWehr  TARosenthal  NE Effects of m-CPP infusions in patients with seasonal affective disorder and healthy controls: diurnal responses and nocturnal regulatory mechanisms. Arch Gen Psychiatry. In press.
Jacobsen  FMMueller  EARosenthal  NERogers  SHill  JLMurphy  DL Behavioral responses to intravenous meta-chlorophenylpiperazine in patients with seasonal affective disorder and control subjects before and after phototherapy. Psychiatry Res. 1994;52181- 197
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 28

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections