It is evident that in the last decade or so, a vast amount of new information has become available concerning the various 5-HT receptor types and their characteristics. This derives from two main research approaches, operational pharmacology, using selective ligands (both agonists and antagonists), and, more recently, molecular biology. Although the scientific community continues to deliberate about the hierarchy of criteria for neurotransmitter receptor characterisation, there seems good agreement between the two approaches regarding 5-HT receptor classification. In addition, the information regarding transduction mechanisms and second messengers is also entirely consistent. Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3. Each group is not only operationally but also structurally distinct, with each receptor group having its own distinct transducing system. The more recently identified 5-HT4 receptor almost undoubtedly represents a fourth 5-HT receptor class on the basis of operational and transductional data, but this will only be definitively shown when the cDNA for the receptor has been cloned and the amino acid sequence of the protein is known. Although those 5-HT receptors that have been fully characterised and classified to date (and, hence, named with confidence) would seem to mediate the majority of the actions of 5-HT throughout the mammalian body, not all receptors for 5-HT are fully encompassed within our scheme of classification. These apparent anomalies must be recognised and need further study. They may or may not represent new groups of 5-HT receptor or subtypes of already known groups of 5-HT receptor. Even though the cDNAs for the 5-ht1E, 5-ht1F, 5-ht5, 5-ht6, and 5-ht7 receptors have been cloned and their amino acid sequence defined, more data are necessary concerning their operational and transductional characteristics before one can be confident of the suitability of their appellations. Therefore, it is important to rationalise in concert all of the available data from studies involving both operational approaches of the classical pharmacological type and those from molecular and cellular biology.(ABSTRACT TRUNCATED AT 400 WORDS)

International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin).

Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A(1), A(2A), A(2B), and A(3). The A(2A) and A(2B) receptors preferably interact with members of the G(s) family of G proteins and the A(1) and A(3) receptors with G(i/o) proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A(3) receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A(1), A(2A), and A(3) expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A(1), A(2A), and A(3) receptors but few drugs that interact selectively with A(2B) receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.

https://pharmrev.aspetjournals.org/content/pharmrev/53/4/527.full.pdf

International Union of Pharmacology. XXV. Nomenclature and Classification of Adenosine Receptors

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on cAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as β-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events.

The Physiology, Signaling, and Pharmacology of Dopamine Receptors

Calcitonin-gene-related peptide (CGRP) and adrenomedullin are related peptides with distinct pharmacological profiles. Here we show that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-transmembrane-domain proteins, which we have called receptor-activity-modifying proteins or RAMPs, are expressed. RAMPs are required to transport CRLR to the plasma membrane. RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor. RAMP2-transported receptors are core-glycosylated and are adrenomedullin receptors.

/pdf/ramps-regulate-the-transport-and-ligand-specificity-of-the-3dt9v953y2.pdf

RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.

G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or “accessory” proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.

/pdf/g-protein-coupled-receptor-allosterism-and-complexing-3fkjazohf8.pdf

G Protein-Coupled Receptor Allosterism and Complexing

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(00)89032-X.pdf

Agonist-receptor efficacy II: agonist trafficking of receptor signals

The recommendations that follow have been updated from the proposals of a Technical Subcommittee set up by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (Jenkinson DH, Barnard EA, Hoyer D, Humphrey PPA, Leff P, and Shankley NP (1995) International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. IX. Recommendations on terms and symbols in quantitative pharmacology. Pharmacol Rev 47:255-266).

/pdf/international-union-of-pharmacology-committee-on-receptor-3i8p99fpqj.pdf

International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures.

https://cdr.lib.unc.edu/downloads/hm50tt91t

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.

https://jpet.aspetjournals.org/content/jpet/early/2010/10/28/jpet.110.173948.full.pdf

Terry P. Kenakin

Papers

G Protein-Coupled Receptor Allosterism and Complexing

Agonist-receptor efficacy II: agonist trafficking of receptor signals

International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

Seven Transmembrane Receptors as Shapeshifting Proteins: The Impact of Allosteric Modulation and Functional Selectivity on New Drug Discovery

Functional Selectivity and Biased Receptor Signaling