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Identification of the low affinity site of the human beta-1-adrenoceptor stimulated by beta-blockers

Reference	BB/C507853/1
Principal Investigator / Supervisor	Professor Stephen Hill
Co-Investigators / Co-Supervisors
Institution	University of Nottingham
Department	Sch of Biomedical Sciences
Funding type	Research
Value (£)	203,623
Status	Completed
Type	Research Grant
Start date	04/01/2005
End date	03/01/2008
Duration	36 months

Abstract

Our recent work on the molecular pharmacology of the human beta 1-adrenoceptor in transfected cell lines has indicated that there are two sites or conformations of the receptor via which certain beta-blockers can interact to produce both agonist and antagonist actions. In the case of the effects of gene transcription the agonist effects of some of these beta-blockers via the secondary site on the receptor can be substantial. The overall aim of the proposal is to investigate the nature of these two sites using site-directed mutagenesis. Key residues that will be investigated include aspartate 138 in transmembrane region three and asparagine 363 in transmembrane region seven of the beta-1 adrenoceptor. A major possibility is that the secondary site of the beta-1 adrenoceptor is produced by receptor homodimerisation. This will be investigated by co-transfection of receptors that contain either a mutation of aspartate 138 or a mutation of asparagine 363 and we will determine whether agonist effects of aryloxypropanolamine beta blockers can be re-established by the receptor dimerisation. In addition, we will also investigate the extent to which the same active state of the receptor can be stabilised by ligands acting at completely different sites within the receptor monomer. Once the nature of the secondary site that binds these beta-blockers has been determined, this will allow the design and synthesis of new drugs that can act specifically at this site.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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