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230 THE AGONIST BIPHASIC DOSE RESPONSE

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230 THE AGONIST BIPHASIC DOSE RESPONSE Powered By Docstoc
					 THE AGONIST BIPHASIC DOSE-RESPONSE CURVE OF THE
HUMAN ALPHA4BETA2 RECEPTOR BECOMES MONOPHASIC
IN THE PRESENCE OF PKC INHIBITORS OR IN LOW LEVELS
          OF EXTRACELLULAR CALCIUM IONS
                       I Bermudez, L.M. Houlihan
                  Oxford Brookes University, Oxford, UK
In the last year it has become widely accepted that the agonist dose-response
curve of human alpha4beta2 (ha4b2) nicotinic acetylcholine (nACh) is
biphasic. However, the molecular basis for the presence of multiple
components in the agonist concentration-response curve, and their
pharmacological nature, have not yet been fully determined, although their
modulation by phosphorylation and chronic exposure to ligands has received
some attention (Mileo, 1995). We have used the potent nicotinic agonist
epibatidine to construct a characteristic two-component dose-response curve
for ha4b2 nACh receptors expressed in oocytes. The two components were
modulated by chronic exposure to both competitive antagonists and
agonists, and by Ca++, in a concentration dependent manner. Nicotine
upregulated the high affinity component, whereas the high affinity
component was abolished by antagonists. To investigate the mechanism
whereby chronic ligand exposure modulated the two components, we used
activators and inhibitors of Protein Kinase C to modify phosphorylation of
the ha4b2 nACh receptor. Inhibition of Protein Kinase C caused a
significant reduction in the size of the high affinity component only. This
study shows that the two components of the epibatidine dose-response curve
for the ha4b2 nACh receptor can be differentially modulated.




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posted:12/1/2011
language:English
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