Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1798, Issue 9, Pages 1821-1828Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2010.05.004
Keywords
Gating current; Roscovitine; Modulation; Markov model; omega-conopeptide
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Funding
- Pennsylvania (PA) Department of Health
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N-type calcium channels play an important role in synaptic transmission and a drug that blocks these channels has become an important tool in controlling chronic pain. The development of new N-channel-targeted drugs is dependent on a better understanding of the gating of these channels and how that gating can be modulated. We have previously concluded that omega-conotoxin GVIA (GVIA) is a gating modifier that acts by destabilizing the N-channel open state. However, this conclusion was largely based on our modeling results and requires experimental support. Roscovitine, a tri-substituted purine, has been shown to stabilize the N-channel open state to slow gating charge relaxation, which provides a direct test of our hypothesis for GVIA-induced gating modification. We found that roscovitine could modulate gating current in the presence of GVIA, which shows that roscovitine can still affect the gating of the GVIA-bound N-channel. However, the magnitude of the roscovitine-induced slowing of Off-gating current was significantly reduced. In addition to confirming our hypothesis, our evidence supports an additional effect of GVIA to alter gating transitions between N-channel closed states. By strongly limiting access to the N-channel open state, GVIA analogs that selectively induce this modulation could provide the basis for the next generation drugs that treat chronic pain. (C) 2010 Elsevier B.V. All rights reserved.
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