Award details

Effect of oligomer formation on agonist signalling at the D2 dopamine receptor

Reference	BB/D016886/1
Principal Investigator / Supervisor	Professor Philip Gordon Strange
Co-Investigators / Co-Supervisors
Institution	University of Reading
Department	Pharmacy
Funding type	Research
Value (£)	287,355
Status	Completed
Type	Research Grant
Start date	02/10/2006
End date	01/10/2009
Duration	36 months

Abstract

This application concerns a study of one of the most important current issues in the biology of G protein coupled receptors, namely the relation of their quaternary structure (dimers/oligomers) to the function of agonists acting at the receptors. The existence of quaternary structure in these receptors is now well established but the functional relevance of this is not well understood. We will investigate, for the D2 dopamine receptor, the hypothesis that this receptor exists in units of a receptor dimer linked to one G protein (R2G) with the units possibly assembling in to larger arrays. This is a new model for the action of this important receptor. The work will be performed using membranes of cells expressing D2 receptors (CHO cells and Sf 9 cells, the latter expressing specific G proteins as well as the receptor in some cases). In these membranes we shall study three aspects of D2 receptor biology in relation to oligomer formation. The binding of agonists to the receptors will be studied using agonist dissociation assays and using agonist binding competition assays. This part of the work should establish that there are cooperative interactions between successive molecules of agonist in binding to D2 receptor oligomers and that these cooperative interactions give rise to particular ligand binding properties. The binding of guanine nucleotides to G proteins will be assessed and the effects of agonists on this will be determined. Agonist signalling will be examined in detail and indications of cooperativity (Hill coefficients less than one seen in preliminary experiments) will be probed in detail. Throughout, the reciprocal interactions between agonists and guanine nucleotides acting on the R2G unit will be probed. Data from these three aspects of the study will be brought together by modelling studies. The R2G model will be set up mathematically and used both to model experimental data and to fit actual data.

Summary

Many human functions depend on the detection of chemical stimuli. Taste and smell are examples where external chemical stimuli are detected by the tongue and nose respectively. Within the body there are other chemical detection systems, for example, in the brain chemical messengers termed neurotransmitters are released and detected and brain function depends on this. The detection of these chemical stimuli depends on the binding of the chemicals to detector proteins termed receptors. The detection process has some similarities to the interaction of a lock and key, the key being the chemical stimulus and the lock being the receptor. These receptors are clearly of critical importance for the normal function of the body but they have a second very important role, in that they are also the sites of action of nearly half the drugs prescribed by doctors. For example, drugs used to treat conditions such as asthma act by binding to these receptors and switching them on whereas drugs used to treat schizophrenia bind to the receptors and switch them off. These receptors have been extensively studied by scientists, and it has recently become apparent that these receptors exist as pairs or larger groups. A group of receptors would be expected to possess different properties as compared to a single receptor. A useful analogy here might be to compare the behaviour of groups of people with the behaviour of an individual person. The relevance of this receptor grouping to the effects of drugs has, however, not been studied very much. In this project, therefore, we intend to study this grouping of receptors and how it affects the ability of drugs to switch receptors on. We intend to look at how the drugs bind to the receptors and how the switching on process is achieved. We also hope to set up ways of predicting the behaviour of the groups of receptors. The idea of receptor grouping has been well established and now is a good time to study the effects of this grouping on drug action. Overall the work will provide new information on how these receptors work and provide new information on these important sites of drug action. The work, therefore, has immense practical importance for understanding the function of these receptors and drug action in general.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Neuroscience and Behaviour
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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