Adrenergic signaling molecular complexes. / Complejos moleculares de la señalización adrenérgica.

Adrenaline and noradrenaline bind to membrane receptors of the superfamily of G protein-coupled receptors (GPCR) in target cells, where they modulate physiological responses such as metabolism, vasoconstriction, vasodilation and proliferation. Alteration in their function is associated with conditions such as hypertension, benign prostatic hyperplasia and cardiac hypertrophy. In response to adrenaline, receptors form signaling complexes, which enables adrenergic action to be specific, rapid and efficient. These signaling complexes or signalosomes are composed of kinases, phosphatases, and adapter and scaffold proteins, which together modulate the receptor function. Manipulation of each protein-protein interaction of the adrenergic signaling complex emerges as a promising therapeutic strategy for the design of drugs that modulate adrenergic action and help to define its pathophysiological significance. An important biological model to perform these investigations is the heart, since it expresses all adrenergic receptors; to date, several heart signalosomes have been described. Mass spectrometry (proteomics), genetic manipulation and biochemical assays, such as two-hybrid and co-immunoprecipitation assays, are tools that are used in these studies.

La adrenalina y la noradrenalina se unen a receptores membranales de la superfamilia de receptores acoplados a proteínas G (GPCR) en las células blanco, donde modulan respuestas fisiológicas tales como el metabolismo, vasoconstricción, vasodilatación y proliferación. La alteración en su función está asociada con hipertensión, hiperplasia prostática benigna e hipertrofia cardiaca. En respuesta a la adrenalina, los receptores forman complejos de señalización, lo que permite que la acción adrenérgica sea específica, rápida y eficiente. Estos complejos de señalización o signalosomas están integrados por cinasas, fosfatasas, proteínas adaptadoras y de andamio, que en conjunto modulan la función del receptor. La manipulación de cada interacción proteína-proteína del complejo de señalización adrenérgico emerge como una estrategia terapéutica prometedora para el diseño de fármacos que modulen la acción adrenérgica y ayuden a definir su significado fisiopatológico. Un modelo biológico importante para realizar estos estudios es el corazón, ya que expresa todos los receptores adrenérgicos; en la actualidad se han descrito varios signalosomas cardiacos. La espectrometría de masas (proteómica), manipulación genética y ensayos bioquímicos como el doble híbrido o la coinmunoprecipitación son herramientas que se emplean en estos estudios.

Probenecid Inhibits α-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature.

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.

Neural control of the circulation.

The purpose of this brief review is to highlight key concepts about the neural control of the circulation that graduate and medical students should be expected to incorporate into their general knowledge of human physiology. The focus is largely on the sympathetic nerves, which have a dominant role in cardiovascular control due to their effects to increase cardiac rate and contractility, cause constriction of arteries and veins, cause release of adrenal catecholamines, and activate the renin-angiotensin-aldosterone system. These effects, as well as the control of sympathetic outflow by the vasomotor center in the medulla and the importance of sensory feedback in the form of peripheral reflexes, especially the baroreflexes, are discussed in the context of cardiovascular regulation.

Timing of the functional diversification of alpha- and beta-adrenoceptors in fish and other vertebrates.

Adrenoceptors (ARs) are G protein-coupled receptors found throughout the vertebrates. Their pharmacology and preliminary phylogenetic analyses suggest that ARs are classified as alpha(1), alpha(2) (and their subtypes), and beta(1), beta(2), and beta(3). However, the relationships among subtypes of this superfamily, as well as both the pattern and the timing of their diversification, are poorly understood. In addition, fish AR subtypes possess pharmacologies and tissue distributions that only partially overlap with those of their mammalian counterparts, in spite of their apparent orthologous relationships within subtypes. Here we analyze 136 sequences in a range of vertebrates, including fish, to resolve these issues. We show that diversification of ARs occurred during duplication events that occurred within distinct time periods. Each period maps to whole-genome duplication events, two in vertebrates and one in fish. We also show that ARs underwent multiple duplications within these broad windows and that fish ARs underwent extensive gene loss after duplications that promoted their functional divergence with respect to other vertebrates.

Noradrenergic regulation of GABAergic inhibition of main olfactory bulb mitral cells varies as a function of concentration and receptor subtype.

The main olfactory bulb (MOB) receives a rich noradrenergic innervation from the pontine nucleus locus coeruleus (LC). Previous studies indicate that norepinephrine (NE) modulates the strength of GABAergic inhibition in MOB. However, the nature of this modulation and the NE receptors involved remain controversial. The goal of this study was to investigate the role of NE receptor subtypes in modulating the GABAergic inhibition of mitral cells using patch-clamp electrophysiology in rat MOB slices. NE concentration dependently and bi-directionally modulated GABA(A) receptor-mediated spontaneous and miniature inhibitory postsynaptic currents (sIPSCs/mIPSCs) recorded in mitral cells. Low doses of NE suppressed sIPSCs and mIPSCs because of activation of alpha2 receptors. Intermediate concentrations of NE increased sIPSCs and mIPSCs primarily because of activation of alpha1 receptors. In contrast, activation of beta receptors increased sIPSCs but not mIPSCs. These results indicate that NE release regulates the strength of GABAergic inhibition of mitral cells depending on the NE receptor subtype activated. Functionally, the differing affinity of noradrenergic receptor subtypes seems to allow for dynamic modulation of GABAergic inhibition in MOB as function of the extracellular NE concentration, which in turn, is regulated by behavioral state.

Distinct role of adrenoceptor subtypes in cardiac adaptation to chronic pressure overload.

1. With the generation of gene knockout (KO) or transgenic overexpression (TG) mouse models targeting adrenoceptors (AR), recent studies in vivo have investigated the role of AR subtypes in pressure overload-induced left ventricular (LV) hypertrophy and remodelling. 2. Although subjecting alpha(1B)-KO mice to transverse aortic constriction (TAC) did not reveal significant phenotype differences compared with controls, mice deficient in both alpha(1A)- and alpha(1B)-AR responded to TAC with poor survival, increased cardiomyocyte apoptosis, more severe fibrosis and dysfunction, but a similar degree of LV hypertrophy, compared with wild-type littermates. Following TAC, alpha(1B)-TG mice developed more severe hypertrophy, interstitial fibrosis and LV dysfunction. In contrast, overexpression of alpha(1A)-AR preserved cardiac function and reduced death from heart failure without affecting the degree of LV hypertrophy. Thus, alpha(1A)- and alpha(1B)-adrenoceptor signalling impacts differently on myocardial adaptation to pressure overload. 3. The absence of both beta(1)- and beta(2)-AR significantly suppressed pressure overload-evoked hypertrophy, fibrosis and expression of inflammatory or fibrogenic genes. Conversely, studies on beta(2)-TG mice with TAC revealed adverse consequences, including accelerated development of heart failure, poor survival and more severe interstitial fibrosis, but a comparable degree of hypertrophy compared with wild-type littermates. 4. Collectively, these findings suggest that the effect of ARs on pressure overload-induced myocardial adaptation is subtype specific. Whereas activation of alpha(1B)-AR or beta(2)-AR contributes to maladaptation and the onset of heart failure, activation of alpha(1A)-AR or inactivation of beta(2)-AR is beneficial in the setting of chronic pressure overload.

Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline.

Presynaptic metabotropic receptors for acetylcholine and adrenaline/noradrenaline were first described more than three decades ago. Molecular cloning has resulted in the identification of five G protein-coupled muscarinic receptors (M(1) - M(5)) which mediate the biological effects of acetylcholine. Nine adrenoceptors (alpha(1ABD),alpha(2ABC),beta(123)) transmit adrenaline/noradrenaline signals between cells. The lack of sufficiently subtype-selective ligands has prevented identification of the physiological role and therapeutic potential of these receptor subtypes for a long time. Recently, mouse lines with targeted deletions for all muscarinic and adrenoceptor genes have been generated. This review summarizes the results from these gene-targeting studies with particular emphasis on presynaptic auto- and heteroreceptor functions of muscarinic and adrenergic receptors. Specific knowledge about the function of receptor subtypes will enhance our understanding of the physiological role of the cholinergic and adrenergic nervous system and open new avenues for subtype-selective therapeutic strategies.

Immunohistochemical localization of adrenergic receptors in the rat organ of corti and spiral ganglion.

Alpha(1)-, beta(1)-, and beta(2)-adrenergic receptors (ARs), which mediate responses to adrenergic input, have been immunohistochemically identified within the organ of Corti and spiral ganglion with polyclonal antibodies of established specificity. Alpha(1)-AR was immunolocalized to sites overlapping supranuclear regions of inner hair cells as well as to nerve fibers approaching the base of inner hair cells, most evident in the basal cochlear turn. A similar preponderance across cochlear turns for alpha(1)-AR in afferent cell bodies in the spiral ganglion pointed to type I afferent dendrites as a possible neural source of alpha(1)-AR beneath the inner hair cell. Foci of immunoreactivity for alpha(1)-AR, putatively neural, were found overlapping supranuclear and basal sites of outer hair cells for all turns. Beta(1)- and beta(2)-ARs were immunolocalized to sites overlapping apical and basal poles of the inner and outer hair cells, putatively neural in part, with immunoreactive nerve fibers observed passing through the habenula perforata. Beta(1)- and beta(2)-ARs were also detected in the cell bodies of Deiters' and Hensen's cells. Within the spiral ganglion, beta(1)- and beta(2)-ARs were immunolocalized to afferent cell bodies, with highest expression in the basal cochlear turn, constituting one possible neural source of receptors within the organ of Corti, specifically on type I afferent dendrites. Beta(1)- and beta(2)-ARs in Hensen's and Deiters' cells would couple to Galphas, known to be present specifically in the supporting cells. Overall, adrenergic modulation of neural/supporting cell function within the organ of Corti represents a newly considered mechanism for modifying afferent signaling.

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: evidence of compensatory changes.

In Alzheimer's disease (AD) there is a significant loss of locus coeruleus (LC) noradrenergic neurons. However, recent work has shown the surviving noradrenergic neurons to display many compensatory changes, including axonal sprouting to the hippocampus. The prefrontal cortex (PFC) is a forebrain region that is affected in dementia, and receives innervation from the LC noradrenergic neurons. Reduced PFC function can reduce cognition and disrupt behavior. Because the PFC is an important area in AD, we determined if noradrenergic innervation from the LC noradrenergic neurons is maintained and if adrenoreceptors are altered postsynaptically. Presynaptic PFC alpha2-adrenoreceptor (AR) binding site density, as determined by 3H-RX821002, suggests that axons from surviving noradrenergic neurons in the LC are sprouting to the PFC of subjects with dementia. Changes in postsynaptic alpha1-AR in the PFC of subjects with dementia indicate normal to elevated levels of binding sites. Expression of alpha1-AR subtypes (alpha1A- and alpha1D-AR) and alpha2C-AR subtype mRNA in the PFC of subjects with dementia is similar to what was observed in the hippocampus with one exception, the expression of alpha1A-AR mRNA. The expression of the alpha1A-AR mRNA subtype is significantly reduced in specific layers of the PFC in subjects with dementia. The loss of alpha1A-, alpha1D- and alpha2C-AR mRNA subtype expression in the PFC may be attributed to neuronal loss observed in dementia. These changes in postsynaptic AR would suggest a reduced function of the PFC. Consequence of this reduced function of the PFC in dementia is still unknown but it may affect memory and behavior.

Genetic variation of human adrenergic receptors: from molecular and functional properties to clinical and pharmacogenetic implications.

Adrenergic receptors (ARs) are directly or indirectly involved in the control of a large panel of physiological functions and are the targets of drugs for the treatment of several common diseases including congestive heart failure, asthma or benign prostatic hyperplasia. The genotyping of human populations with diverse ethnicity has revealed that the genes encoding alpha(1A)-, alpha(1B)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)- and beta(3)-AR are polymorphic in their coding region as well as in their regulatory domains and non-coding regions. The functional consequences of these genetic variations include changes in expression at transcriptional or translational level, modification of coupling to heterotrimeric G-proteins resulting in a gain or a loss in function, and alteration of GRK-mediated receptor phosphorylation/desensitization or of agonist-promoted down-regulation. None of the mutations identified so far is per se a major risk factor for acquired or inherited disease; however, variants of alpha(2C)-AR and beta(1)-AR may act in synergy to determine the progression of heart failure and certain combinations of polymorphisms on beta(2)-AR correlate with asthmatic phenotypes or response to beta(2)-agonist therapy. Herein we summarize the present knowledge on AR gene polymorphisms, and discuss the putative consequences of variations resulting in receptor malfunction on pharmacogenomics and disease predisposition.

Quantitative mRNA analysis of adrenergic receptor subtypes in the intestines of healthy dairy cows and dairy cows with cecal dilatation-dislocation.

OBJECTIVE: To investigate the distribution of mRNA coding for 9 adrenoceptor subtypes in the intestines of healthy dairy cows and cows with cecal dilatationdislocation (CDD). SAMPLE POPULATION: Full-thickness specimens of the intestinal wall were obtained from the ileum, cecum, proximal loop of the ascending colon (PLAC), and external loop of the spiral colon (ELSC) of 15 cows with CDD (group 1) and 15 healthy (control) cows (group 2, specimens collected during laparotomy; group 3, specimens collected after slaughter). PROCEDURES: Concentrations of mRNA for 9 adrenoceptor subtypes (alpha(1A), alpha(1B), alpha(1D), alpha(2AD), alpha(2B), alpha(2C), beta(1), beta(2), and beta(3)) were measured by quantitative real-time reverse transcriptase-PCR assay. Results were expressed relative to mRNA expression of a housekeeping gene. RESULTS: Expression of mRNA for alpha(1B)-, alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors was significantly lower in cows with CDD than in control cows. In the ileum, these receptors all had lower mRNA expression in cows with CDD than in control cows. The same effect was detected in the ELSC for mRNA for alpha(2AD)-, alpha(2B)-, beta(1)-, and beta(2)-adrenoceptors, and in the cecum and PLAC for alpha(2B)- and beta(2)-adrenoceptors. Groups did not differ significantly for alpha(1A)-adrenoceptors. The mRNA expression for alpha(1D)-, alpha(2C)-, and beta(3)-adrenoceptors was extremely low in all groups. CONCLUSIONS AND CLINICAL RELEVANCE: Differences in expression of mRNA coding for adrenoceptors, most pronounced in the ileum and spiral colon, between cows with CDD and control cows support the hypothesis of an implication of adrenergic mechanisms in the pathogenesis of CDD in dairy cows.

[Influence of adrenoreceptors on functions of the body]. / Adrenoreceptoriu poveikis organizmo funkcijoms.

The remarkably diverse effects of the catecholamines and similar sympathomimetic agents are directly related to an understanding of the classification and different types of adrenoreceptors. Characteristics and physiological regulatory mechanisms of the receptor result in variable response of organ systems to catecholamines stimulation. Different adrenoreceptors regulate distinct physiological processes by controlling the synthesis or release of a variety of second messengers. The goal of this review was to turn one's attention to the below mentioned aspects. There are three known subtypes of each alpha1-, alpha2- and beta-adrenoreceptor types. Structure of the adrenoreceptors, which belong to subtypes of the same receptor type, is similar and structure of the adrenoreceptors of the separate types is very different. Genetic peculiarities of the receptors may influence liability to some diseases. Acting on the adrenoreceptors may change function of many organs and may serve for the treatment of cardiovascular, respiratory tract diseases and allergic reactions. Selective acting on the adrenoreceptors of the separate subtypes may have the different effect on the organs. Great consideration is given for that property in the development of new drugs: substitution by different chemical radicals leads to increasing selectivity for the separate subtypes of the adrenoreceptors. The prolonged use of the adrenomimetics may lead to refractoriness.

Adrenergic receptor characterization of CA1 hippocampal neurons using real time single cell RT-PCR.

The CA1 region of the rat hippocampus exhibits both alpha and beta adrenergic receptor (AR) responses, however, the specific AR subtypes involved and the neuronal expression patterns for these receptors are not well understood. We have employed single cell real time RT-PCR in conjunction with cell-specific immunohistochemical markers to determine the AR expression patterns for hippocampal neurons located in CA1, a region often implicated in learning and memory processes. Cytoplasmic samples were taken from 55 individual cells located in stratum oriens, pyramidale, or radiatum and reverse transcribed. All successfully amplified pyramidal neuron samples (n = 17) expressed mRNA for the beta2AR, with four cells additionally expressing mRNA for the beta1AR subtype. Positive interneurons from stratum oriens (n = 10) and stratum radiatum (n = 8) expressed mRNA for the alpha1A and/or alpha(1B)AR (n = 9/18) only when coexpressing transcripts for somatostatin. Interneurons containing neuropeptide Y or cholecystokinin (n = 9/18) were not positive for any of the nine AR subtypes, suggesting that CA1 interneuron AR expression is limited to a subset of somatostatin-positive cells. These findings suggest that only a select number of AR subtypes are transcriptionally expressed in CA1 and that these receptors are selective to specific neuronal cell types.

GPCRsclass: a web tool for the classification of amine type of G-protein-coupled receptors.

The receptors of amine subfamily are specifically major drug targets for therapy of nervous disorders and psychiatric diseases. The recognition of novel amine type of receptors and their cognate ligands is of paramount interest for pharmaceutical companies. In the past, Chou and co-workers have shown that different types of amine receptors are correlated with their amino acid composition and are predictable on its basis with considerable accuracy [Elrod and Chou (2002) Protein Eng., 15, 713-715]. This motivated us to develop a better method for the recognition of novel amine receptors and for their further classification. The method was developed on the basis of amino acid composition and dipeptide composition of proteins using support vector machine. The method was trained and tested on 167 proteins of amine subfamily of G-protein-coupled receptors (GPCRs). The method discriminated amine subfamily of GPCRs from globular proteins with Matthew's correlation coefficient of 0.98 and 0.99 using amino acid composition and dipeptide composition, respectively. In classifying different types of amine receptors using amino acid composition and dipeptide composition, the method achieved an accuracy of 89.8 and 96.4%, respectively. The performance of the method was evaluated using 5-fold cross-validation. The dipeptide composition based method predicted 67.6% of protein sequences with an accuracy of 100% with a reliability index > or =5. A web server GPCRsclass has been developed for predicting amine-binding receptors from its amino acid sequence [http://www.imtech.res.in/raghava/gpcrsclass/ and http://bioinformatics.uams.edu/raghava/gpersclass/ (mirror site)].

Functional adrenergic receptor polymorphisms and idiopathic orthostatic intolerance.

OBJECTIVES: Idiopathic orthostatic intolerance (IOI) is a common disorder that is characterized by chronic orthostatic symptoms and substantial increases in heart rate and plasma norepinephrine concentrations that are disproportionately high while standing. Several features of the syndrome, including the tachycardia, tremulousness, and exaggerated norepinephrine have been considered potentially due to hypoactive or hyperactive states of adrenergic receptors of the sympathetic nervous system. The aim of this study was therefore to ascertain whether genotypes at eight polymorphic loci within five relevant adrenergic receptor genes (alpha2A, alpha2B, alpha2C, beta1 and beta2) influence the risk for IOI. METHODS: We studied 80 young men in military service (20 patients with IOI and 60 age-matched controls). All participants underwent a tilt table test including monitoring of blood pressure, heart rate and plasma catecholamines, in the supine position and during 30 min of standing. Genotyping at the eight loci (alpha2ALys251, alpha2BDel301-303, alpha2CDel322-325, beta1Gly49, beta1Arg389, beta2Arg16, beta2Glu27, beta2Ile164) was performed in all participants. Chi-square tests of independence were used to test for associations between IOI and genotype. In addition, an association of the polymorphisms with haemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way variance analysis. RESULTS: For the beta1Gly49 polymorphism we found a decrease in the risk of IOI among persons who were homozygous (odds ratio, 0.88; 95% confidence interval, 0.81-0.97). In addition, we found an association between beta1Gly49 and decreased heart rate in the upright position, regardless of IOI diagnosis. There were no associations with the other studied polymorphisms and IOI. CONCLUSIONS: Our current results suggest that the beta1Gly49 polymorphism is protective for IOI. This is likely one of several common genetic loci that may represent modifiers of IOI phenotypes.

Adrenergic targets for the treatment of cognitive deficits in schizophrenia.

RATIONALE: The cognitive functions of the prefrontal cortex (PFC) are profoundly impaired in schizophrenic patients. Although dopamine has been the major focus of schizophrenia research, norepinephrine (NE) also has marked influences on PFC cognitive functioning. OBJECTIVE: This review aims to identify the adrenergic receptors which may be appropriate targets for therapeutic actions in schizophrenia. METHODS: Studies of adrenergic mechanisms influencing PFC function in animals and humans were reviewed. RESULTS: Modest levels of NE engage postsynaptic alpha(2A)-adrenergic receptors and strengthen working memory. These beneficial effects have been observed at both the behavioral and cellular levels in animals, and have translated to the clinic in patients with PFC impairments. Thus, the alpha(2A)-adrenergic receptor is a proven molecular target. In contrast, high levels of NE released during stress impair PFC cognitive function via activation of protein kinase C intracellular signaling, a pathway increasingly associated with the etiology of schizophrenia. Blockade of alpha(1) adrenoceptors or inhibition of protein kinase C helps to protect PFC cognitive function in animals, and may have similar therapeutic actions in humans. Blockade of the alpha(2C) receptor may also be helpful in enhancing catecholamine release while blocking detrimental DA actions in striatum. CONCLUSION: Highly selective adrenergic agents may be useful for enhancing PFC function in schizophrenic patients

Astrocytic adrenoceptors: a major drug target in neurological and psychiatric disorders?

Considerable attention has recently been paid to astrocyte functions, which are briefly summarized. A large amount of data is available about adrenoceptor expression and function in astrocytes, some of it dating back to the 1970's and some of it very recent. This material is reviewed in the present paper. The brain is innervated by noradrenergic fibers extending from locus coeruleus in the brain stem, which in turn is connected to a network of adrenergic and noradrenergic nuclei in the medulla and pons, contributing to the control of (nor)adrenergic, serotonergic, dopaminergic and cholinergic function, both in the central nervous system (CNS) and in the periphery. In the CNS astrocytes constitute a major target for noradrenergic innervation, which regulates morphological plasticity, energy metabolism, membrane transport, gap junction permeability and immunological responses in these cells. Noradrenergic effects on astrocytes are essential during consolidation of episodic, long-term memory, which is reinforced by beta-adrenergic activation. Glycogenolysis and synthesis of glutamate and glutamine from glucose, both of which are metabolic processes restricted to astrocytes, occur at several time-specific stages during the consolidation. Astrocytic abnormalities are almost certainly important in the pathogenesis of multiple sclerosis and in all probability contribute essentially to inflammation and malfunction in Alzheimer's disease and to mood disturbances in affective disorders. Noradrenergic function in astrocytes is severely disturbed by chronic exposure to cocaine, which also changes astrocyte morphology. Development of drugs modifying noradrenergic receptor activity and/or down-stream signaling is advocated for treatment of several neurological/psychiatric disorders and for neuroprotection. Astrocytic preparations are suggested for study of mechanism(s) of action of antidepressant drugs and pathophysiology of mood disorders.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.