Biomedical subjects

Steven M Foord

Publications and source records attributed to Steven M Foord.

5 recordsLinked to original sources

PubMed2003

Matching accessories.

Heterodimerization enhances the complexity of ligand recognition and diversity of signaling responses of heterotrimeric guanine nucleotide-binding protein-coupled receptors (GPCRs). Many accessory proteins (for ion channels or GPCRs) appear to associate with their partners relatively early in the process whereby proteins are transported to the cell surface; their roles in modulating function may have evolved out of simple proximity to a protein that once upon a time they either facilitated or accompanied through the maturation process. The receptor activity-modifying proteins (RAMPs) are a family of single-transmembrane accessory proteins that heterodimerize with GPCRs and, thereby, allow individual GPCRs to recognize multiple ligands and to activate various signaling pathways in response to ligand binding. The M10 family of major histocompatibility complex (MHC) class 1b proteins has recently been shown to associate with murine vomeronasal V2R receptors, as well as to escort them to the cell surface. The exact role of M10 in modulating V2R function (or vice versa) remains to be determined.

Animals↗

PubMed2003

Important amino acids for the function of the human MT1 melatonin receptor.

Models of G protein-coupled melatonin receptor structure suggest that ligand recognition occurs in a binding pocket formed by transmembrane helices III, V and VII. Constitutively active mutations in G protein-coupled receptors have revealed that transmembrane helix III/intracellular loop 2 interface and transmembrane domain VI are critical regions in receptor activation. In this study, nine site-directed mutants of the human MT1 melatonin receptor were created to test the importance of specific amino acids in these regions in ligand recognition and receptor activation events. We analyzed ligand binding, G protein activation and subcellular localization of MT1 receptors transiently expressed in COS-7 cells. Receptor ELISA was employed to study expression levels of N-terminally HA epitope tagged wild-type and mutant MT1 receptors. Mutations in histidine H195 (His(5.46)) in transmembrane domain V reduced receptor affinity for 2-[125I]iodomelatonin. Several other mutants had diminished expression on the plasma membrane. Amino acids M107 (Met(3.32)) in transmembrane domain III and S280 (Ser(7.46)) in transmembrane domain VII were found not to participate in ligand recognition in human MT1 receptor. Constitutive activity was not obtained with mutations in N124 (Asn(3.49)) or P253 (Pro(6.50)). These mutants failed to bind 2-[125I]iodomelatonin and had reduced expression levels. The need to upgrade current melatonin receptor models has become evident. Several important amino acids for the human MT1 melatonin receptor function were revealed in the current study, with effects of mutations ranging from slightly reduced affinity or efficacy to complete loss of function.

Amino Acids↗

PubMed2003

Molecular identification of high and low affinity receptors for nicotinic acid.

Nicotinic acid has been used clinically for over 40 years in the treatment of dyslipidemia producing a desirable normalization of a range of cardiovascular risk factors, including a marked elevation of high density lipoprotein and a reduction in mortality. The precise mechanism of action of nicotinic acid is unknown, although it is believed that activation of a G(i)-G protein-coupled receptor may contribute. Utilizing available information on the tissue distribution of nicotinic acid receptors, we identified candidate orphan receptors. The selected orphan receptors were screened for responses to nicotinic acid, in an assay for activation of G(i)-G proteins. Here we describe the identification of the G protein-coupled receptor HM74 as a low affinity receptor for nicotinic acid. We then describe the subsequent identification of HM74A in follow-up bioinformatics searches and demonstrate that it acts as a high affinity receptor for nicotinic acid and other compounds with related pharmacology. The discovery of HM74A as a molecular target for nicotinic acid may facilitate the discovery of superior drug molecules to treat dyslipidemia.

Amino Acid Sequence↗

PubMed2002

Receptor classification: post genome.

Most of the G-protein-coupled receptors (GPCRs) in the human genome have been described. Investigation will now shift from discovery to analysis. Like many other genes, those encoding GPCRs are frequently found adjacent to each other in clusters. Duplicated genes often share ligands, signalling pathways and amino acid sequence. But, GPCRs do not have to be adjacent to be similar to each other. Phylogenetic analysis divides Family A GPCRs into many clusters that, more often than not, share similar types of ligands. Communication of these types of data for hundreds of GPCRs requires a robust and accepted nomenclature, Locus Link symbols are suggested.

Computational Biology↗

PubMed2002

International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors.

The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.

Animals↗