Subscribe Now Subscribe Today
Review Article
 

Applications of G Protein-coupled Receptors in Clinical Medicine



D. Ramakrishna and P. Rao
 
Facebook Twitter Digg Reddit Linkedin StumbleUpon E-mail
ABSTRACT

Progress in areas of research from the field of G Protein Coupled Receptor (GPCR) signalling, now shows that GPCRs are involved in a broad range of cellular regulatory activities. By virtue of widespread distribution and important roles in cell physiology and biochemistry, GPCRs play multiple important roles in clinical medicine. The understanding of how the GPCR interact (G proteins and effectors, as well as other regulatory proteins) thus has enormous implications for clinical medicine. The rapid progress in determining three-dimensional structures of GPCRs and more recently their regulators and effectors, has illuminated the search for mechanisms of activation and regulation and has allowed structure-based mutagenesis to test these ideas. The structural and mechanistic studies will in the future also hopefully provide opportunities to alter those interactions in pathological situations. A compilation of the most relevant research topics about the implication of heterotrimeric G proteins in the etiology of genetics and neurobiology of mood will provide a broad perspective of this potential therapeutic target field. In this review, we tried to show how far GPCR research involved in recent medicine.

Services
Related Articles in ASCI
Search in Google Scholar
View Citation
Report Citation

 
  How to cite this article:

D. Ramakrishna and P. Rao, 2011. Applications of G Protein-coupled Receptors in Clinical Medicine. Current Research in Neuroscience, 1: 15-23.

DOI: 10.3923/crn.2011.15.23

URL: https://scialert.net/abstract/?doi=crn.2011.15.23
 
Received: November 06, 2010; Accepted: November 12, 2010; Published: April 29, 2011



INTRODUCTION

G-protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants and so have great potential as therapeutic targets for a broad spectrum of diseases. They are also fascinating molecules from the perspective of membrane-protein structure and biology. Great progress has been made over the past three decades in understanding diverse GPCRs, from pharmacology to functional characterization in vivo. More than a thousand such receptors are known and more are being discovered all the time. Heterotrimeric G proteins transduce ligand binding to these receptors into intracellular responses, which underlie physiological responses of tissues and organisms. GPCR, also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor (Hamm, 1998). G protein-linked receptors (GPLR), comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal transduction pathways and ultimately, cellular responses. GPCRs are found only in eukaryotes, including yeast, choanoflagellates (King et al., 2003) and animals. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones and neurotransmitters and vary in size from small molecules to peptides to large proteins. GPCRs are involved in many diseases and are also the target of approximately 30% of all modern medicinal drugs (Overington et al., 2006).

G-protein-coupled receptors (GPCR) have well-recognized roles in clinical medicine. Their expression on the plasma membrane makes GPCR readily accessible, especially by hydrophilic hormones and drugs, including both agonists and antagonists and their non-uniformity of expression in different tissues and cell types provides selectivity (in some cases, specificity) in the targeting of these receptors for the activation or blockade of physiological events. Studies in recent years have provided a number of new insights, many of them gleaned from application of the tools of the genetic revolution (Insel et al., 2007). In this review, we have covered GPCR structure and classification, signal transduction, physiological role and various disorders related to GPCR structural dysfunction and neurobiology of mood disorders. The primary focus of this review will be to summarize recent advances and applications of GPCR in clinical medicine, which will help the researchers.

STRUCTURE

GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly-conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein. In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved (Palczewski et al., 2000). In 2007, the first structure of a human GPCR was solved (2R4R, 2R4S) (Rasmussen et al., 2007). This human β2-adrenergic receptor GPCR structure, proved to be highly similar to the bovine rhodopsin in terms of the relative orientation of the seven-transmembrane helices.

SIGNAL TRANSDUCTION

There are two principal signal transduction pathways involving the G protein-coupled receptors: the cAMP signal pathway and the Phosphatidylinositol signal pathway (Gilman, 1987). When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G-protein by exchanging its bound GDP for a GTP. The G-protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signalling proteins or target functional proteins directly depending on the a subunit type (Gαs, Gαi, Gαq/11, Gα12/13).

GPCRs were classified into 6 classes based on sequence homology and functional similarity (class A to F) (Attwood and Findlay, 1994; Foord et al., 2005; Kolakowski, 1994). The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19) (Joost and Methner, 2002). More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed (Bjarnadottir et al., 2006).

PHYSIOLOGICAL ROLES

The human genome encodes thousands of G protein-coupled receptors (Vassilatis et al., 2003), about 350 of which detect hormones, growth factors and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions. They comprise the largest family of receptors in the human genome.

Table 1: Examples of rare mutants of GPCR that cause human diseases
Image for - Applications of G Protein-coupled Receptors in Clinical Medicine

One such critical action is in the visual system where rhodopsin in photoreceptor-capturing neurons, retinal rods and color (red, blue and green) opsins in retinal cones, transduce the input from photons of light into electrical impulses that then travel to the brain and are decoded. A second major class of physiologically important GPCR are those that mediate the action of hormones, especially polypeptide hormones but also including the action of such hormones, such as the calcium-sensing receptor or other chemical entities (e.g., lipids, amines, fatty acids). A third class is receptors for physiologically important neurotransmitters, such as norepinephrine (and to a lesser extent, epinephrine), acetylcholine (at muscarinic cholinergic receptors), dopamine, serotonin (at certain receptors), glutamate (at metabotropic receptors) as well as numerous peptides and lipids that function as neuromodulators. In addition, a number of hormonally responsive GPCR have been identified as pathologic entities in a variety of endocrine disorders such as Autosomal Dominant Hypocalcemia (ADH), Hirschsprung’s disease, Cryptorchidism etc., (Table 1). The latter disorders include those with either activating mutations or mutations that block hormonal response. 7-TM receptors are the target of around half of all modern medicinal drugs. Their expression on the cell surface makes them readily accessible to hydrophilic drugs and their non-uniform expression provides selectivity in activating or blocking physiological events. Agonists and antagonists of 7-TM receptors are used in the treatment of disease in almost every organ system.

INHERITED DISORDERS OF GPCR

Genetic diseases and genetic variants associated with those diseases are generally quite rare, occurring in <1% of the population and often variably among subjects of different ethnicities. non-lethal mutations can occur in GPCR, especially those that are expressed in sensory and hormonal systems, where they serve as mediators of information transfer from the extracellular environment to the cell interior (Fredriksson and Schioth, 2005). To date, mutations that lead to human disease have been identified in a relatively limited number of GPCR. Typically disease can be caused by: (Insel et al., 2007).

Non-functional receptors (GHRH and familial growth hormone deficiency)
Constitutive activation (Rhodopsin and retinitis pigmentosa)
Changes in ligand binding specificity (Thyroid-stimulating hormone receptor and hyperthyroidism of pregnancy)
Improper receptor processing (vasopressin receptor and diabetes insipidus)
Antibodies directed against the receptors (Thyroid stimulation hormone receptor and Graves disease)
Constitutively active or inactive G proteins

A large number of monogenic mutations have been identified in rhodopsin, in particular in patients that have the disease retinitis pigmentosa. Rhodopsin belongs to Family A, which contains the largest group of GPCR super family members; receptors in this Family generally contain a relatively short extracellular N-terminus and highly conserved amino acids within each transmembrane domain. Family A members are activated by small ligands such as biogenic amines and nucleotides, although rhodopsin itself is stimulated by photons of light that activate a retinal bound in a transmembrane pocket, which highlights the sites that are mutated in rhodopsin, a wide variety of residues have been identified in patients with retinitis pigmentosa, a leading cause of blindness and visual disability in younger people that occurs with an overall frequency of one in 4000.

The V2 receptor belongs to Family B, whose receptors recognize large peptides. Nephrogenic Diabetes Insipidus (NDI), which results from failure of vasopressin (antidiuretic hormone, ADH) to act on the renal collecting duct to facilitate water reabsorption, is another well-studied monogenic disorder of a GPCR. Mutations in the arginine vasopressin receptor 2 (AVPR2, V2), causes congenital nephrogenic diabetes insipidus in ~90% of patients via an X-linked recessive mode of inheritance. In most cases, these mutations lead to the intracellular trapping of the V2 receptors, such that few receptors reach the plasma membrane to trigger the activation of Gs and adenylyl cyclase and thereby, the generation of cAMP.

Genetic disorders of the Calcium-Sensing Receptor (CaSR) are a third example of a monogenic disease in GPCR (Tfelt-Hansen et al., 2005). This receptor is found on numerous tissues involved in calcium homeostasis, including the parathyroid glands, kidney and intestine. Binding of calcium to the CaSR is the mechanism by which parathyroid cells detect changes in ionized calcium concentration and in turn, modulate parathyroid hormone secretion so as to maintain normal serum calcium levels. CaSRs in renal tubules modulate calcium reabsorption in response to alterations in extracellular calcium concentrations. Several hypocalcemic and hypercalcemic disorders have been identified that derive from rarely occurring mutations of CaSR: loss-of-function CaSR mutations in the hypercalcemic disorders of familial benign (hypocalciuric) hypercalcaemia (FHH, FBH or FBHH) and neonatal severe primary hyperparathyroidism (NSHPT) (each of which occur <1/10,000) and gain-of-function CaSR mutations in autosomal dominant hypocalcaemia with hypercalciuria (ADHH) and Bartter’s syndrome type V.

In addition to such “classical” monogenic diseases, another type of such disease can involve the generation of antibodies as monoclonal (or polyclonal) expansion of immune cells with the antibody products directed against GPCR or in some cases, their downstream targets. The most prevalent example is Graves disease, a form of hyperthyroidism with enhanced response to Thyroid-Stimulating Hormone (TSH) that is most commonly secondary to autoimmune activation of TSH receptors (Schott et al., 2005).

Table 2: Examples of polymorphisms of GPCR associated with human diseases
Image for - Applications of G Protein-coupled Receptors in Clinical Medicine

Another example of activating (as well as inhibitory) antibodies directed at GPCR (e.g., β-adrenergic and muscarinic cholinergic) is Chagas’ cardiomyopathy, which is triggered by infection with the protozoan Trypanosoma cruzi (Kierszenbaum, 2005).

In several other settings, antibodies directed at GPCR can blunt hormone action, preventing G-protein activation (Jahns et al., 2006; Wallukat et al., 2000). Of note, such disorders are almost invariably ones that occur in adults rather than children whereas monogenic disorders of the receptors themselves often manifest clinical abnormalities much earlier in life.

Genetic variants/polymorphisms identified in GPCRs can influence receptor expression, targeting, function and receptor turnover; as well as the ability of receptors to recognize and respond to pharmacologic agents. Some of important sequence variants identified in human GPCR genes that relate to human diseases such as Hypertension, Obesity, Haplotype associated with schizophrenia etc. listed in Table 2.

NEUROBIOLOGY OF MOOD DISORDERS

Suicide is a one of the major mood disorders and it is a leading cause of death (Joiner et al., 2005). As per a recent report from Centers for Disease Control and Prevention (CDC) in the United States in 2002, suicide was the eleventh most common cause of death (in 1998 it was the eight most common cause) (Licinio and Wong, 2005). One of the first studies showing a clear relation between suicide and psychiatric diseases reported that 45% of the suicide victims suffered mood disorders and 23% alcoholism (Robins et al., 1959). Thus, several researchers have demonstrated that depression, alcoholism, drugs of abuse and schizophrenia are the psychiatric pathologies more commonly related to suicide (Cheng, 1995; Isometsa and Lonnqvist, 1998; Rodriguez-Puertas et al., 1996). Depression is another major cause of suicide. In this regard, mood disorders seem to be present in at least 50% of all suicide victims (Balazs et al., 2003; Henriksson et al., 1993).

Several hypotheses have linked the pathogenesis of depression to alterations in the neurotransmission systems in the central nervous system (Ramakrishna et al., 2008). During the last four decades, alterations in the serotonergic and/or noradrenergic neurotransmission have been related to mood disorders. This monoaminergic theory of depression was based on several reports (Bunney and Davis, 1965; Coppen, 1969; Schildkraut, 1965).

GPCRs are involved in cellular responses to the majority of hormones and neurotransmitters and represent an enormously significant target for drug discovery. Alterations associated with depressive disorders of certain GPCR subtypes, such as a-adrenoceptor (Devaki et al., 2006; Subhash et al., 2003) and their subtypes (Ramakrishna et al., 2004; Ramakrishna and Subhash, 2010), 5-HT1A serotonin (Subhash and Ramakrishna, 2006) μ-opioid (Escriba et al., 2004; Gabilondo et al., 1995) and CB1 cannabinoid (Hungund et al., 2004) receptor, both in terms of density and functionality, have been reported using different approaches.

Drug discovery in depression has been limited by the lack of a universally accepted animal model that can be used to screen for antidepressant effects. Although there are several animal models that reproduce some features of depression, their relevancy to the specifically human disorder major depression has been debated (Wong and Licinio, 2004).

Several works have reported that the antidepressant drugs modulate the density of different heterotrimeric G proteins (Lesch et al., 1991a; Lesch and Manji, 1992), as well as their functional response (Delgado et al., 1990; Menkes et al., 1983; Okada et al., 1986). Experimental evidences have shown that lithium attenuates the GPCR-induced modulation of the second messengers, even in the absence of changes in the density of the receptor (Devaki et al., 2006). It has been consistently reported that chronic lithium affects G protein function (Avissar et al., 1988; Colin et al., 1991; Drummond, 1988; Lesch et al., 1991b).

CONCLUSION

GPCR are physiologically important in maintaining normal homeostasis, in particular via their ability to mediate responses to circulating hormones and neurotransmitter input in the central, peripheral and autonomic nervous systems.

The cellular mechanisms of action of many antidepressants are still unknown and many depressed patients do not respond to antidepressant therapy. By understanding the cellular and molecular alterations associated with depressive disorders, the design of more efficacious therapeutic chemicals could be achievable. Several discrepancies have been reported in the literature according to the possible alterations in G proteins associated with mood disorders.

PCR will continue to be highly important in clinical medicine because of their large number, wide expression and role in physiologically important responses. We speculate that future discoveries will reveal new GPCR drugs which will help the genetic and various neurological disorders. In addition, further insights into GPCR biology may reveal novel, unexpected therapeutic targets that influence the GPCR life cycle or “ligand directed signalling”.

REFERENCES

1:  Attwood, T.K. and J.B. Findlay, 1994. Fingerprinting G-protein-coupled receptors. Protein Eng., 7: 195-203.
PubMed  |  Direct Link  |  

2:  Avissar, S., G. Schreiber, A. Danon and R.H. Belmaker, 1988. Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex. Nature, 331: 440-442.
PubMed  |  

3:  Balazs, J., Y. Lecrubier, N. Csiszer, J. Kosztak and I. Bitter, 2003. Prevalence and comorbidity of affective disorders in persons making suicide attempts in Hungary: Importance of the first depressive episodes and of bipolar II diagnoses. J. Affect Disord., 76: 113-119.
Direct Link  |  

4:  Bjarnadottir, T.K., D.E. Gloriam, S.H. Hellstrand, H. Kristiansson, R. Fredriksson and H.B. Schioth, 2006. Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics, 88: 263-273.
CrossRef  |  Direct Link  |  

5:  Bunney, W.E. Jr. and J.M. Davis, 1965. Norepinephrine in depressive reactions. A review. Arch. Gen. Psychiatry, 13: 483-494.
PubMed  |  

6:  Cheng, A.T., 1995. Mental illness and suicide. A case-control study in East Taiwan. Arch. Gen. Psychiatry, 52: 594-603.
PubMed  |  

7:  Colin, S.F., H.C. Chang, S. Mollner, T. Pfeuffer, R.R. Reed, R.S. Duman and E.J. Nestler, 1991. Chronic lithium regulates the expression of adenylate cyclase and Gi-protein alpha subunit in rat cerebral cortex. Proc. Natl. Acad. Sci. USA., 88: 10634-10637.
PubMed  |  

8:  Coppen, A., 1969. Defects in monoamine metabolism and their possible importance in the pathogenesis of depressive syndromes. Psychiatr. Neurol. Neurochir, 72: 173-180.
PubMed  |  

9:  Delgado, P.L., D.S. Charney, L.H. Price, G.K. Aghajanian, H. Landis and G.R. Heninger, 1990. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch. Gen. Psychiatry, 47: 411-418.
PubMed  |  

10:  Devaki, R., S.S. Rao and S.M. Nadgir, 2006. The effect of lithium on the adrenoceptor-mediated second messenger system in the rat brain. J. Psychiatry Neurosci., 31: 246-252.
Direct Link  |  

11:  Drummond, A.H., 1988. Lithium affects G-protein receptor coupling. Nature, 331: 388-388.
CrossRef  |  

12:  Escriba, P.V., A. Ozaita and J.A. Garcia-Sevilla, 2004. Increased mRNA expression of alpha2A-adrenoceptors, serotonin receptors and mu-opioid receptors in the brains of suicide victims. Neuropsychopharmacology, 29: 1512-1521.
PubMed  |  

13:  Foord, S.M., T.I. Bonner, R.R. Neubig, E.M. Rosser and J.P. Pin et al., 2005. International union of pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev., 57: 279-288.
CrossRef  |  Direct Link  |  

14:  Fredriksson, R. and H.B. Schioth, 2005. The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol. Pharmacol., 67: 1414-1425.
CrossRef  |  Direct Link  |  

15:  Gabilondo, A.M., J.J. Meana and J.A. Garcia-Sevilla, 1995. Increased density of mu-opioid receptors in the postmortem brain of suicide victims. Brain Res., 682: 245-250.
PubMed  |  

16:  Gilman, A.G., 1987. G proteins: Transducers of receptor-generated signals. Annu. Rev. Biochem., 56: 615-649.
Direct Link  |  

17:  Hamm, H.E., 1998. The many faces of G protein signaling. J. Biol. Chem., 273: 669-672.
CrossRef  |  Direct Link  |  

18:  Henriksson, M.M., H.M. Aro, M.J. Marttunen, M.E. Heikkinen, E.T. Isometsa, K.I. Kuoppasalmi and J.K. Lonnqvist, 1993. Mental disorders and comorbidity in suicide. Am. J. Psychiatry, 150: 935-940.
PubMed  |  

19:  Hungund, B.L., K.Y. Vinod, S.A. Kassir, B.S. Basavarajappa and R. Yalamanchili et al., 2004. Upregulation of CB1 receptors and agonist-stimulated [35S] GTPgammaS binding in the prefrontal cortex of depressed suicide victims. Mol. Psychiatry, 9: 184-190.
PubMed  |  

20:  Insel, P.A., C.M. Tang, I. Hahntow and M.C. Michel, 2007. Impact of GPCRs in clinical medicine: Monogenic diseases, genetic variants and drug targets. Biochim. Biophys. Acta., 1768: 994-1005.
CrossRef  |  Direct Link  |  

21:  Isometsa, E.T. and J.K. Lonnqvist, 1998. Suicide attempts preceding completed suicide. Br. J. Psychiatry, 173: 531-535.
Direct Link  |  

22:  Jahns, R., V. Boivin and M.J. Lohse, 2006. Beta 1-adrenergic receptor-directed autoimmunity as a cause of dilated cardiomyopathy in rats. Int. J. Cardiol., 112: 7-14.
PubMed  |  Direct Link  |  

23:  Joiner, T.E. Jr., J.S. Brown and L.R. Wingate, 2005. The psychology and neurobiology of suicidal behavior. Annu. Rev. Psychol., 56: 287-314.
Direct Link  |  

24:  Joost, P. and A. Methner, 2002. Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biol., 3: 1-16.
Direct Link  |  

25:  Kierszenbaum, F., 2005. Where do we stand on the autoimmunity hypothesis of Chagas disease. Trends Parasitol., 21: 513-516.
CrossRef  |  

26:  King, N., C.T. Hittinger and S.B. Carroll, 2003. Evolution of key cell signaling and adhesion protein families predates animal origins. Science, 301: 361-363.
CrossRef  |  Direct Link  |  

27:  Kolakowski, L.F. Jr., 1994. GCRDb: A G-protein-coupled receptor database. Receptors Channels, 2: 1-7.
PubMed  |  Direct Link  |  

28:  Lesch, K.P., C.S. Aulakh, T.J. Tolliver, J.L. Hill and D.L. Murphy, 1991. Regulation of G proteins by chronic antidepressant drug treatment in rat brain: Tricyclics but not clorgyline increase Go alpha subunits. Eur. J. Pharmacol., 207: 361-364.
PubMed  |  

29:  Lesch, K.P., C.S. Aulakh, T.J. Tolliver, J.L. Hill, B.L. Wolozin and D.L. Murphy, 1991. Differential effects of long-term lithium and carbamazepine administration on Gs alpha and Gi alpha protein in rat brain. Eur. J. Pharmacol., 207: 355-359.
PubMed  |  

30:  Lesch, K.P. and H.K. Manji, 1992. Signal-transducing G proteins and antidepressant drugs: Evidence for modulation of alpha subunit gene expression in rat brain. Biol. Psychiatry, 32: 549-579.
PubMed  |  

31:  Licinio, J. and M.L. Wong, 2005. Depression, antidepressants and suicidality: A critical appraisal. Nat. Rev. Drug Discov., 4: 165-171.
PubMed  |  

32:  Menkes, D.B., M.M. Rasenick, M.A. Wheeler and M.W. Bitensky, 1983. Guanosine triphosphate activation of brain adenylate cyclase: Enhancement by long-term antidepressant treatment. Science, 219: 65-67.
PubMed  |  

33:  Okada, F., Y. Tokumitsu and M. Ui, 1986. Desensitization of beta-adrenergic receptor-coupled adenylate cyclase in cerebral cortex after in vivo treatment of rats with desipramine. J. Neurochem., 47: 454-459.
PubMed  |  

34:  Overington, J.P., B. Al-Lazikani and A.L. Hopkins, 2006. How many drug targets are there. Nature Rev. Drug Discov., 5: 993-996.
Direct Link  |  

35:  Palczewski, K., T. Kumasaka, T. Hori, C.A. Behnke and H. Motoshima et al., 2000. Crystal structure of rhodopsin: A G protein-coupled receptor. Sci., 289: 739-745.
CrossRef  |  Direct Link  |  

36:  Ramakrishna, D. and M.N. Subhash, 2010. Differential modulation of alpha-1 adrenoceptor subtypes by antidepressants in the rat brain. J. Neural Transm.,

37:  Ramakrishna, D., M.N. Subhash and S. Sharada, 2008. Differential effect of specific antidepressants on a1-adrenoceptors in rat brain. J. Neurochem., 106: 43-46.

38:  Ramakrishna, D., M.N. Subhash and S. Sharada, 2004. Modulation of a1-adrenoceptors by tricyclic antidepressants in rat brain. J. Neurochem., 88: 77-80.

39:  Rasmussen, S.G., H.J. Choi, D.M. Rosenbaum, T.S. Kobilka and F.S. Thian et al., 2007. Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature, 450: 383-387.
CrossRef  |  Direct Link  |  

40:  Robins, E., G.E. Murphy, R.H. Wilkinson Jr., S. Gassner and J. Kayes, 1959. Some clinical considerations in the prevention of suicide based on a study of 134 successful suicides. Am. J. Public Health Nations Health, 49: 888-899.
Direct Link  |  

41:  Rodriguez-Puertas, R., J. Pascual and A. Pazos, 1996. Effects of freezing storage time on the density of muscarinic receptors in the human postmortem brain: An autoradiographic study in control and Alzheimers disease brain tissues. Brain Res., 728: 65-71.
CrossRef  |  

42:  Schildkraut, J.J., 1965. The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am. J. Psychiatry, 122: 509-522.
Direct Link  |  

43:  Schott, M., W.A. Scherbaum and N.G. Morgenthaler, 2005. Thyrotropin receptor autoantibodies in Graves disease. Trends Endocrinol. Metab., 16: 243-248.
CrossRef  |  

44:  Subhash, M.N. and D. Ramakrishna, 2006. Effect of sumatriptan on cortical 5-HT1B adrenoceptors in rat brain. J. Cell Tissue Res., 6: 743-747.

45:  Subhash, M.N., M.R. Nagaraja, S. Sharada and K.Y. Vinod, 2003. Cortical alpha-adrenoceptor downregulation by tricyclic antidepressants in the rat brain. Neurochem. Int., 43: 603-609.
PubMed  |  

46:  Tfelt-Hansen, J., A. Ferreira, S. Yano, D. Kanuparthi, J.R. Romero, E.M. Brown and N. Chattopadhyay, 2005. Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells. Am. J. Physiol. Endocrinol. Metab., 288: E1206-E1213.
Direct Link  |  

47:  Vassilatis, D.K., J.G. Hohmann, H. Zeng, F. Li and J.E. Ranchalis et al., 2003. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl. Acad. Sci. USA., 100: 4903-4908.
PubMed  |  Direct Link  |  

48:  Wallukat, G., E. Nissen, R. Morwinski and J. Muller, 2000. Autoantibodies against the beta- and muscarinic receptors in cardiomyopathy. Herz, 25: 261-266.
PubMed  |  Direct Link  |  

49:  Wong, M.L. and J. Licinio, 2004. From monoamines to genomic targets: A paradigm shift for drug discovery in depression. Nat. Rev. Drug Discov., 3: 136-151.
Direct Link  |  

©  2021 Science Alert. All Rights Reserved