Channels
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The antianginal drug ranolazine exerts voltage- and use-dependent block (UDB) of several Na+ channel isoforms, including Na(v) 1.4. We hypothesized that ranolazine will similarly inhibit the paramyotonia congenita Na(v) 1.4 gain-of-function mutations, R1448C, R1448H, and R1448P that are associated with repetitive action potential firing. Whole-cell Na+ current (I(Na)) was recorded from HEK293 cells expressing the hNa(v) 1.4 WT or R1448 mutations. ⋯ In computer simulations, 3 µM ranolazine inhibited the sustained and excessive firing of skeletal muscle action potentials that are characteristic of myotonia. Taken together, the data indicate that ranolazine interacts with the open state and stabilizes the inactivated state(s) of Na(v)1.4 channels, causes voltage- and use-dependent block of I(Na) and suppresses persistent I(Na). These data further suggest that ranolazine might be useful to reduce the sustained action potential firing seen in paramyotonia congenita.
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Gain-of-function mutations in CaV 2.1 (P/Q-type) Ca2+ channels cause familial hemiplegic migraine type 1 (FHM1), a subtype of migraine with aura. Knockin (KI) mice carrying FHM1 mutations show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. ⋯ In contrast, blockade of N- or R-type Ca2+ channels has only a small inhibitory effect on CSD threshold and velocity of propagation. Our findings support a model in which Ca2+ influx through presynaptic P/Q-type Ca2+ channels with consequent release of glutamate from recurrent cortical pyramidal cell synapses and activation of NMDA receptors are required for initiation and propagation of the CSD involved in migraine.