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S Avissar

Publications and source records attributed to S Avissar.

At least 37 records · Page 2Linked to original sources
PubMed1991

Magnesium reversal of lithium inhibition of beta-adrenergic and muscarinic receptor coupling to G proteins.

Recently, lithium was found to inhibit the coupling of both muscarinic cholinergic and beta-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins respectively. These findings suggest that G proteins are the common site for both the antimanic and antidepressant therapeutic effects of lithium. Magnesium ions are crucial to the function of G proteins and interact with them at multiple sites. In the present study using rat cerebral cortex, we determined that magnesium can reverse the ability of lithium to inhibit isoprenaline- and carbamylcholine-induced increases in guanosine triphosphate (GTP) binding to G proteins. Lithium concentrations effective in attenuating G protein function were found to be hyperbolically dependent on free Mg2+ concentrations, suggesting multiple sites of competition between lithium and magnesium on G proteins. Free intracellular Mg2+ concentrations in rat cerebral cortex in vivo are known to be less than 1 mM. At such Mg2+ concentrations, therapeutically efficacious lithium concentrations (1 to 1.5 mM) were still able to alter G protein function, which supports the physiological and clinical relevance of lithium action on G proteins.

Animals↗
PubMed1991

Lithium administered by eye drops: a better treatment for bipolar affective disorder?

1. Bipolar affective patients are supersensitive to light. 2. Lithium treatment decreases retinal sensitivity to light. 3. Recent findings concerning lithium perturbation of the function of various members of the G proteins family including transducin (G1), as well as findings of lithium sensitive hyperactive G proteins in mononuclear leukocytes of patients with mania led to the hypothesis that lithium sensitive hyperfunctional G1 is responsible for the supersensitivity to light in affective patients. 4. Thus, a change in the usual route of lithium administration into eye drops delivery is hypothesized to be more efficient clinically, with the advantages of shortening the time delay necessary to achieve therapeutic effects, and having less systemic side effects and reduced toxicity.

Bipolar Disorder↗
PubMed1991

Lithium sensitive G protein hyperfunction: a dynamic model for the pathogenesis of bipolar affective disorder.

Guanine nucleotide binding proteins (G proteins) play a pivotal role in information transduction from various membrane receptors to a variety of intracellular effector systems. By influencing the metabolism of adenylate cyclase and phosphatidylinositol, G proteins affect the activities of both cAMP-dependent protein kinase (kinase A) and protein kinase C. The hypothesis of this present study addresses the oscillatory behavior of symptoms observed in manic-depressive patients by suggesting that the cellular phosphorylation state in the central nervous system, which results from the relative activity of protein kinase A and protein kinase C, determines the affective state. From this hypothesis, we developed a kinetic model based on self- and inter-regulatory steps between these two protein kinase systems. The solutions of the differential equations governing this kinetic model can describe oscillatory pathological affective states. More specifically, we show that hyperfunction of G proteins leads to an unstable 'catastrophic' dynamic system characteristic of a manic or depressive state, and that lithium treatment attenuates G protein function and damps the oscillatory system to yield a stable state.

Bipolar Disorder↗
PubMed1990

Carbamazepine and electroconvulsive shock attenuate beta-adrenoceptor and muscarinic cholinoceptor coupling to G proteins in rat cortex.

We have recently found that lithium attenuates the function of G proteins, suggesting these proteins as the common site for both the antimanic and antidepressant therapeutic effects of lithium. Perturbation of G protein function may thus be a general characteristic of treatments effective in bipolar affective disorder. In the present study, we demonstrate that both chronic carbamazepine and repeated electroconvulsive shock treatment inhibit the coupling of both muscarinic cholinoceptors and beta-adrenoceptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively.

Animals↗
PubMed1990

Carbamylcholine inhibits beta-adrenergic receptor-coupled Gs protein function proximal to adenylate cyclase.

The specific mechanism by which the inhibitory guanine nucleotide binding protein (Gi) mediates the inhibition of adenylate cyclase activity is still unclear. The subunit dissociation model, based on studies in purified or reconstituted systems, suggests that the beta gamma subunit, which is dissociated with activation of Gi, inhibits the function of the stimulatory guanine nucleotide binding protein (Gs) by reducing the concentration of the free alpha s subunit. In the present study, Gs protein function is determined by measuring cholera toxin-blockable, isoproterenol-induced increases in guanosine triphosphate (GTP) binding capacity to rat cardiac ventricle membrane preparations. Carbamylcholine totally inhibited this beta-adrenergic receptor-coupled Gs protein function. Pretreatment of the cardiac ventricle membrane with pertussis toxin prevented this muscarinic agonist effect. These results confirm the possibility of an inhibitory agonist-receptor coupled effect through Gi on Gs protein function proximal to the catalytic unit of adenylate cyclase in an intact membrane preparation.

Adenosine Diphosphate Ribose↗
PubMed1990

Lithium-selective alteration of the function of brain versus cardiac Gs protein.

Lithium was recently demonstrated to inhibit the coupling of both muscarinic cholinergic receptors and beta-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively, thus suggesting alteration of the function of G protein by lithium, as the single site for both the antimanic and antidepressant effects of this drug. One of the most puzzling aspects of the ability of lithium to ameliorate the manic-depressive condition, is its relatively selective action upon the central nervous system (CNS). In the present study, it was shown that lithium selectively attenuated the function of Gs proteins in the CNS, assessed through isoproterenol-induced increases in the binding of guanosine triphosphate (GTP) to these proteins. Therapeutic concentrations of lithium (1-1.5 mM in vitro) inhibited the function of Gs protein in the cerebral cortex of the rat, while 4- to 6-fold larger concentrations of lithium were required to alter the function of Gs protein equivalently in the cardiac ventricles of the rat. Chronic administration of lithium via rat chow, containing lithium carbonate, to rats totally abolished the effect of isoproterenol on the binding of GTP in the CNS but did not affect the function of peripheral cardiac Gs protein. The lithium-selective action on the function of Gs protein in the CNS may stem from the heterogeneity of the alpha s subunit proteins: in the heart, the major species is a 45 kDa molecule, while in the brain, a 52 kDa molecular weight species predominates. The heterogeneity in alpha s subunits may thus be the biochemical basis for the selective action of lithium on the CNS and for the scarcity of peripheral side effects.

Adenosine Diphosphate Ribose↗
PubMed1990

Role of inositol-1-phosphatase inhibition in the mechanism of action of lithium.

Li inhibition of noradrenergic adenylate cyclase may be due to inhibition by Li of agonist-induced increases in GTP binding to G-protein. Such inhibition by Li of G-protein function could have effects on phosphatidyl-inositol-mediated second messenger systems as well as on cyclic AMP-mediated systems. However, Sherman, Berridge and others have proposed that Li affects phosphatidylinositol metabolism by inhibiting inositol-1-phosphatase. We recently have been able to measure inositol-1-phosphatase in human red blood cells. Preliminary data on patients treated with Li compared with controls suggests that the enzyme is indeed inhibited in vivo in patients undergoing Li treatment. However, a series of experiments in rats on addition of inositol to Li treatment did not find that inositol could reverse Li effects. Chronic oral high dose inositol does not reverse Li-induced polyuria (measured by polydipsia), Li-induced weight loss or Li-induced depression of exploratory behavior. These results suggest that Li inhibition of inositol-1-phosphatase indeed occurs in vivo. However, the physiological significance of inositol-1-phosphatase inhibition is not yet established.

Animals↗
PubMed1989

Muscarinic receptor subclassification and G-proteins: significance for lithium action in affective disorders and for the treatment of the extrapyramidal side effects of neuroleptics.

The classification of muscarinic receptors into M1 and M2 subtypes and the involvement of guanine nucleotide binding proteins (G-proteins) as major mediators of receptor information transduction in the cholinergic and other neurotransmitter systems have prompted us to undertake studies both at receptor and postreceptor levels that may shed light on the importance of these new findings to the pharmacotherapy of manic-depressive illness and of extrapyramidal syndromes. We searched for patterns of muscarinic selectivity among the commonly used anticholinergics (biperiden, procyclidine, trihexyphenidyl, benztropine, and methixen) through radioligand receptor studies in various rat tissues. The drugs showed a range of selectivity, from the totally nonselective methixen to the highly M1-selective biperiden. Sinus arrhythmia measurements were undertaken in psychiatric patients treated with different antiparkinsonian anticholinergics. The extent of sinus arrhythmia suppression was inversely correlated with the degree of M1 selectivity of the drugs used, advocating the use of M1-selective antiparkinsonian anticholinergics like biperiden in the treatment of extrapyramidal side effects. The implications of muscarinic receptor subclassification were further extended to include postreceptor phenomena. We have directly studied G-protein function by measuring cholinergic agonist-induced increases in guanosine triphosphate (GTP) binding to these proteins. This cholinergic agonistic effect was shown to be exerted by G-proteins other than Gs (the adenylate cyclase stimulatory G-protein), i.e., Gi (the adenylate cyclase inhibitory G-protein) or Gp [the G-protein activating phosphatidylinositol (PI) turnover], as ribosylation by pertussis toxin abolished this cholinergic effect, whereas it was unaffected by cholera toxin. Pertussis toxin-blockable, carbamylcholine-induced increases in GTP binding capacity were found to be mediated through M1 muscarinic receptors, as M1-selective antagonists were 100-fold more effective than M2 selective antagonists in blocking carbamylcholine effects. Moreover, carbamylcholine effect was exclusively detected in tissues predominantly populated by M1 receptors. Our results thus suggest that carbamylcholine-induced increases in GTP binding are exerted through M1 receptors interacting with Gp. At therapeutically efficacious concentrations, lithium completely blocked carbamylcholine-induced increases in GTP binding capacity in both in vitro and in vivo experiments.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex.

Lithium is a unique drug with therapeutic as well as prophylactic value for both manic and depressive phases of manic-depressive illness. The precise mechanisms of its clinical efficacy remain unknown, but there are two main theories of its biochemical action. One proposes that lithium inhibits adrenergically activated adenylate cyclase function whereas the other suggests that it inhibits phosphatidyl inositol turnover, which is known to be activated by cholinergic agonists. Neither mechanism alone, however, can explain both the antimanic and antidepressant effects of lithium. Because of the pivotal role of G proteins in post-receptor information transduction, we have investigated the interaction of lithium with G protein function. Lithium at therapeutically efficacious concentrations completely blocked both adrenergic and cholinergic agonist-induced increases in [3H]GTP binding to membranes from rat cerebral cortex, in both in vitro and ex vivo experiments. The same lithium treatments also abolished guanine nucleotide modulation of agonist binding. Our findings suggest G proteins (Gs and Gi or Go) as the molecular site of action for both the antimanic and antidepressant effects of lithium.

Animals↗
PubMed1987

Osmotic enhancement of mitogenic stimulation in PNA-negative murine thymocytes.

Increasing the osmolarity of the culture medium enhances the response of peanut agglutinin (PNA)-negative thymocytes to stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA), interleukin 1 (IL-1) and interleukin 2 (IL-2) in the presence of phytohemagglutinin (PHA). The effect was attained by the addition to the medium of salts such as NaCl and KCl or by addition of nonionized compounds such as sucrose and fucose. The enhanced response was monitored by determination of [3H]thymidine incorporation, IL-2 production, and blasts formation. The potentiating effect of hypertonic medium on PNA-negative thymocytes treated with PHA and TPA was most pronounced at suboptimal concentrations of PHA. Hypertonic medium did not enhance the response of thymocytes treated with TPA and supraoptimal concentrations of PHA. Increasing the osmolarity of the medium 44 hr after initiation of culture did not enhance [3H]thymidine incorporation in thymocytes that were pulsed between 52 and 72 hr. The enhancing effect of increased osmolarity in mitogenic stimulation of thymocytes may be related to osmotic activation of the Na+/H+ antiport.

Animals↗
PubMed1986

Early effects of TPA on protein kinase activity in murine thymocytes. Reduction of protein kinase C activity in the cytosol and increase of Ca2+ and phospholipid-independent kinase activity in the particulate fractions.

Brief treatment of intact thymocytes with TPA and other tumor promoters causes a reduction in protein kinase C activity from the cytosol and an increase in kinase activity in the particulate fraction. In contrast to the activity in the cytosol, which is absolutely dependent on the addition of Ca2+, phosphatidylserine and diolein, the activity in the particulate fraction is independent of these agents. Analysis of target specificity of the particulate kinase activity using exogenous and endogenous substrates suggests that the increased phosphorylation in the particulate fraction is catalysed by protein kinase C with altered catalytic properties. Although interleukin-1 and TPA are both co-mitogens for murine thymocytes, interleukin-1 does not share with TPA its property to alter protein kinase activity in the cytosolic and particulate fractions.

Animals↗
PubMed1985

Selective effects of TPA and IL-1 on protein phosphorylation in murine thymocytes.

Protein kinase C activity was demonstrated in murine thymocytes and the effects of TPA and IL-1 on this enzyme were studied. TPA, but not IL-1, could substitute for diacylglycerol in protein kinase C activation. Although TPA and IL-1 are both potent comitogens for murine thymocytes they markedly differ in their effects on protein phosphorylation and protein kinase C activation. Treatment of intact thymocytes with TPA resulted in a marked increase in the phosphorylation of an endogenous protein with Mr approximately 44,000. Enhanced phosphorylation of this protein was also observed when protein kinase C was activated in thymocyte extracts. In contrast to TPA, IL-1 neither induced phosphorylation of the 44,000-Da protein nor activated protein kinase C. The data suggests that protein kinase C does not mediate the comitogenic effect of IL-1 in murine thymocytes.

Animals↗
PubMed1983

Oligomeric structure of muscarinic receptors is shown by photoaffinity labeling: subunit assembly may explain high- and low-affinity agonist states.

The potent muscarinic photoaffinity reagent N-methyl-4-piperidyl p-azidobenzilate (azido-4NMPB) was used to covalently label specific muscarinic binding sites in various brain regions and in the heart. In the cortex and hippocampus, a single specifically labeled protein with an apparent molecular mass of 86,000 daltons was detected by gel electrophoresis. In the medulla pons, cerebellum, and cardiac atria, there was a 160,000-dalton band in addition to the 86,000-dalton polypeptide. Under certain conditions, alkali or hydroxylamine treatment dissociated both macromolecules into a single 40,000-dalton polypeptide. These results suggest that the muscarinic receptor exists in oligomeric forms and that a dimer and tetramer of a basic 40,000-dalton peptide may exist as interconvertible species. We propose a model to explain the biological architecture of the muscarinic receptors and suggest a possible correlation between the azido-4NMPB-labeled polypeptides and the two states of the receptor observed in agonist binding experiments.

Affinity Labels↗
PubMed1982

Affinity labeling of muscarinic receptors in rat cerebral cortex with a photolabile antagonist.

Highly potent photoaffinity probes for muscarinic binding sites were prepared by the incorporation of an azido group into the benzilic acid moiety in two compound, 3-quinuclidinyl benzilate (3QNB) and N-methyl-4-piperidyl benzilate (4NMPB). Inactivation of muscarinic sites in rat cortex depends on the formation of a reversible complex with the azides prior to their photolytic conversion to the highly reactive nitrenes. During photolysis, radiolabeled azido-4NMPB interacted specifically and with high affinity (Kd = 1.06 nM) with the muscarinic receptors, and the ligand could be covalently incorporated into a macromolecule of about 86,000 Mr, presumably the muscarinic receptor. The incorporation was almost stoichiometric when compared to determination of receptor density by reversible ligands. Atropine (10 microM) afforded specific protection (greater than 83%) of the receptor against inactivation by azido-[3H]4NMPB. This compound and the other ligands described here (i.e., amino-4NMPB, amino-3QNB, and azido-3QNB) represent powerful potential probes for the biochemical isolation and characterization of muscarinic receptors.

Affinity Labels↗
PubMed1982

Muscarinic mechanisms and sex hormone secretion in rat adenohypophysis and preoptic area.

The highly specific tritiated muscarinic antagonist N-methyl-4-piperidyl benzilate [(3H)-4NMPB] was used in direct binding and in competition experiments with the muscarinic agonist oxotremorine to investigate the influence of in vivo endocrine manipulations involving estrogen on muscarinic receptors in the adenohypophysis and hypothalamus. In the adenohypophysis the characteristics of antagonist binding in ovariectomized female rats, like those in androgenized females, resembled those in normal male rats; this trend was reversed in ovariectomized females after implantation of 17 beta-estradiol capsules, with the characteristics of antagonist binding now resembling those in normal female rats at estrus. Agonist binding characteristics also showed some distinct differences between treated and normal female rats: the proportion of high affinity binding sites decreased both in ovariectomized and androgenized rats, while the affinity of these sites became greater as compared to control animals. The results clearly show that changes in the levels of sex steroids, as a result of the above-mentioned endocrine manipulations, influence the behavior of the muscarinic receptors in both areas, and suggest muscarinic participation in the regulation of gonadotropin release in the hypothalamus-pituitary-ovary axis.

Animals↗