Regulation and desensitisation studies on the nicotinic acid receptors

RM Therapeutics. Pharmacology

Mustafa, Sanam ; Milligan, Graeme

University:University of Glasgow

Department:Institute of Molecular Cell and Systems Biology

关键词: nicotinic acid receptors, HM74, HM74A, nicotinic acid, G protein-coupled receptors, desensitisation, regulation;   

Others  :  http://theses.gla.ac.uk/510/1/2008MustafaPhd.pdf

来源: University of Glasgow

【 摘 要 】

The lipid-modifying qualities of nicotinic acid, a B3 vitamin, have been exploited for many years to prevent cardiovascular disease and its associated mortality. Despite its widespread availability and clinical use, the clinical target and precise molecular mechanism by which nicotinic acid acts remains elusive. In order to maximise nicotinic acid’s full potential as a lipid-modulating drug, overcome its related side effects and further develop novel and more potent drugs it is vital to understand its molecular mechanism of action. Fifty years on from its arrival on the market, receptors which this drug acts upon have recently been identified as the G protein-coupled ‘nicotinic acid receptors’.A family of three highly homologous receptors, HM74, HM74A and GPR81 are characterised by their differing affinities for nicotinic acid. Comparison of these homologues revealed a high degree of similarity between them, with the greatest similarity between HM74 and HM74A. The main structural difference between these receptors is the longer C-terminal tail of HM74. As the C-terminal tail of GPCRs is often implicated in receptor regulation it was hypothesised that the differences in this region may result in differential regulation of HM74 and HM74A. This hypothesis was tested by examining the regulation and desensitisation characteristics of each receptor in a heterologous expression system. Both HM74 and HM74A failed to interact with β-arrestin 2 or internalise in response to nicotinic acid. However, both receptors were phosphorylated in an agonist-dependent manner. HM74 but not HM74A was demonstrated to desensitise as result of prolonged nicotinic acid exposure. The importance of the C-terminal region was further analysed by the use of chimeric nicotinic acid receptors, in which the C-terminal tail of HM74 and HM74A were exchanged. It was shown that the C-terminal tail of HM74 may be implicated in the desensitisation characteristics of this receptor. Furthermore, it was shown that HM74 and HM74A display differential characteristics with respect to ERK1/2 phosphorylation.