Impact of GPCRs in clinical medicine: Monogenic diseases, genetic variants and drug targets

Insel, Paul A.; Tang, Chih‐Min; Hahntow, Ines N.; Michel, Martin C.

doi:10.1016/j.bbamem.2006.09.029

Cited by 155 publications

(127 citation statements)

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“…GPCR protein detection may also be helpful to identify which cell type within a tissue expresses a given receptor and/or in which subcellular component receptors are found. Moreover, the expression density of GPCR at the cell surface is not a static entity but rather dynamically regulated by a variety of physiological and pathophysiological conditions as well as drug treatment (Insel et al 2007). A better understanding of such regulation also often requires specific quantification of expression at the protein level.…”

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confidence: 99%

How reliable are G-protein-coupled receptor antibodies?

Michel

Wieland

Tsujimoto

2009

Naunyn-Schmied Arch Pharmacol

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A cluster of manuscripts in this issue of the Journal highlights a lack of selectivity of 49 antibodies against 19 subtypes of α 1 -and β-adrenoceptors, muscarinic, dopamine and galanin receptors as well as vanilloid (TRPV1) receptors. Taken together these data demonstrate that lack of selectivity appears to be the rule rather than the exception for antibodies against G-protein-coupled and perhaps also other receptors. Thus, the previously often applied validation of such antibodies by the disappearance of staining in the presence of blocking peptide, i.e. the antigen against which the antibody was raised, alone is insufficient to demonstrate specificity. We propose that receptor antibodies should be validated by at least one of the following techniques: a) disappearance of staining in knock-out animals of the target receptor, b) reduction of staining upon knock-down approaches such as siRNA treatment, c) selectivity of staining in immunoblots or immunocytochemistry for the target receptor vs. related subtypes when expressed in the same cell line and/or d) antibodies raised against multiple distinct epitopes of a receptor yielding very similar staining patterns. Other issues of consideration to obtain reliable results based on receptor antibodies in applications such as immunohistochemistry or immunoblotting are also being discussed.

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mentioning

confidence: 99%

How reliable are G-protein-coupled receptor antibodies?

Michel

Wieland

Tsujimoto

2009

Naunyn-Schmied Arch Pharmacol

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272

200

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“…In addition, these receptors, through G protein-dependent and -independent mechanisms, can link to an array of intracellular signalling pathways that can in turn regulate a plethora of physiological functions. Not surprisingly therefore, GPCRs are almost universally expressed in cells/tissues and specific manipulation of their activity is the primary target of approximately 50% of presently available drugs [10,11,12]. It is also becoming increasingly apparent that GPCRs sometimes exhibit cell-and tissue-specific signalling, regulatory and/or pharmacological properties [13].…”

Section: Introductionmentioning

confidence: 99%

“…It is also becoming increasingly apparent that GPCRs sometimes exhibit cell-and tissue-specific signalling, regulatory and/or pharmacological properties [13]. Genetic variation (single nucleotide polymorphisms), post-translational modification (including phosphorylation, glycosylation and lipidation) as well as association with accessory proteins may contribute to such "phenotypic" diversity [11,13]. However, much accruing evidence also indicates that alternative splicing of GPCRs can profoundly affect signalling, regulatory and/or pharmacological properties.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Markovic

Challiss

2009

Cell. Mol. Life Sci.

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Abstract. The G protein-coupled receptors (GPCRs) are a superfamily of transmembrane receptors that have a broad distribution and can collectively recognize a diverse array of ligands. Activation or inhibition of GPCR signalling can affect many (patho)physiological processes and consequently they are a major target for existing and emerging drug therapies.A common observation has been that the pharmacological, signalling and regulatory properties of GPCRs can vary in a cell-and tissue-specific manner. Such "phenotypic" diversity might be attributable to post-translational modifications and/or association of GPCRs with accessory proteins, however, post-transcriptional mechanisms are also likely to contribute. Although, approximately 50% of GPCR genes are intronless, those that possess introns can undergo alternative splicing, generating GPCR subtype isoforms that may differ in their pharmacological, signalling and regulatory properties. In this Review we shall highlight recent research into GPCR splice-variation, and discuss the potential consequences this might have for GPCR function in health and disease.

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“…Twenty percent of them are point mutations that cause improper folding, transport or processing of the receptor. 56 Mutations that cause the diseases are often nonsense mutations that lead to a single amino acid substitution in the peptide chain of the receptor. Taking into account the effects of mutations on rhodopsin receptor activity, they can be divided into two groups: a) mutations leading to an increase of receptor activity by creating constitutively active mutants (CAM).…”

Section: Characteristics Of Selected Gpcr In Disease Statementioning

confidence: 99%

Role of GPCRs towards Cell: An explanation of G-Protein Coupled Receptor Structure

Raj¹

2017

JSRT

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G-protein coupled receptors are the heptahelical, serpentine receptor and are multifunctional receptors having modulatory activity of a wide variety of biological process including: Neurotransmission, Chemoattraction, Cardiac function, Olfaction and Vision etc. At largest level they are involved in signal transduction across cell membranes therefore they represent major targets in the development of novel drug candidates in all clinical areas. Particularly membrane cholesterol has been reported to have a great role in the functioning of a number of GPCRs. Apart from this it also have some drawbacks. Mutations that occur are associated with a broad spectrum of diseases of diverse etiology. As a mutations result, there is a change in receptor activity (GPCR become inactive, overactive, or constitutively active), in the process of ligand binding and signal transduction. Changes in the GPCRs functioning can cause diseases such as retinitis pigmentosa (rhodopsin mutations), nephrogenic diabetes insipidus (vasopressin receptor mutations), and obesity (melanocortin receptor mutations). Keywords Brief introduction of 'G' ProteinG-Protein is composed of 3 subunits alpha, beta and gaama. These G-Protein binds to the Guanosine Triphosphate (GTP) present in the receptor. Alpha and gaama subunits are linked to membrane by covalently attached lipids. The alpha subunits associate to GPCRs only when in GDP mode. G-Proteins in inactive state bound to the GDP then it moves and get bound to the GTP then after binding it gets activated. Alpha subunit of G-Protein has GTPase activity. Discovery, detection of GPCRsAs we know that the molecular properties of 7 TM receptors has been discovered over the past 40 years. However, rhodopsin had been identified as a photosensitive pigment as early as the 1870s, and its covalent ligand retinal was reported in 1933.9 From the century ago we know about the ligand-activated receptors, in these receptors reactive cells act as a 'receptive substance' on the surface.10,11 Early experiments with tissue preparations measured the responses to stimulators (agonists) and inhibitors (antagonists). 12There are so many signalling compounds present inside the cells. These include the second messenger cyclic AMP (cAMP) and the enzyme adenylyl cyclase (; 13 Nobel Prize in Physiology or Medicine 1971 to Earl W. Sutherland, Jr.), cAMP-dependent protein kinase 14 and heterotrimeric G-proteins, [15][16][17] Nobel Prize in Physiology or Medicine 1994 to Martin Rodbell and Alfred G. Gilman).The nature of the ligand-activated receptors remained controversial up to the 1970s. Epinephrine is an important hormone and neurotransmitter that influences many different physiological processes, e.g. regulation of heart rate and blood pressure. Cells responsive to epinephrine have specific plasma membrane receptors (adrenergic receptors) that interact with the hormone. There are at least nine different adrenergic receptors, grouped as α-and β-receptors. Different tissues and organs respond in different manners to...

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Impact of GPCRs in clinical medicine: Monogenic diseases, genetic variants and drug targets

Cited by 155 publications

References 123 publications

How reliable are G-protein-coupled receptor antibodies?

How reliable are G-protein-coupled receptor antibodies?

Alternative splicing of G protein-coupled receptors: physiology and pathophysiology

Role of GPCRs towards Cell: An explanation of G-Protein Coupled Receptor Structure

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