Statedependent calcium channel antagonism

Voltage-gated calcium channels fluctuate between three primary functional states, which provide the opportunity for selective pharmacological intervention [10]. Initially, when the membrane is hyperpolarized, the channel is in the resting (closed) state. In response to the appropriate depolarized membrane potential, the channel may undergo a conforma-tional change to the activated state (open), permitting Ca + ions to enter the cell through the channel. Finally, the channel may enter an inactivated conformational state from either the activated or the resting state. In this inactivated state, the channel remains unresponsive to a depolarizing potential until it transitions to the closed state (recovers). Increased neuronal firing rates, such as those in chronic pain syndromes or epileptic episodes, are believed to drive a greater proportion of calcium channels into the inactivated state [11]. These distinct conformational states afford the possibility of discovering state-dependent calcium channel antagonists that block neuronal transmission only under conditions of hyper-excitability. By contrast, state-independent antagonists block calcium channels under most conditions of electrical excitability, and this latter mechanism forms the basis of a variety of naturally occurring peptidyl neurotoxins [12]. State-dependent blockers may be identified using laborintensive patch-clamp electrophysiology techniques or by using more recently developed high-throughput Fluorometric Imaging Plate Reader (FLIPR) assays [13-15].

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