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Modulation of Single Channels Underlying Hippocampal L-Type Current Enhancement by Agonists Depends on the Permeant Ion

¹Department of Pharmacology and Medical Research Council Centre for Synaptic Plasticity, University of Bristol, Bristol BS8 1TD, United Kingdom; ²Department of Pharmacology, University of Tennessee, Memphis, Tennessee 38163; and ³Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262

Submitted 21 July 2003; accepted in final form 29 March 2004

The influx of calcium (Ca²⁺) ions through L-type channels underlies many cellular processes, ranging from initiation of gene transcription to activation of Ca²⁺-activated potassium channels. L-type channels possess a diagnostic pharmacology, being enhanced by the dihydropyridine BAY K 8644 and benzoylpyrrole FPL 64176. It is assumed that the action of these compounds is independent of the ion conducted through the channel. In contrast to this assumption, modulation of L-type channel activity in acutely dissociated rat CA1 hippocampal neurons depended on the divalent ion identity. BAY K 8644 and FPL 64176 substantially increased single-channel open time only when barium (Ba²⁺) was the permeant ion. BAY K 8644 increased single-channel conductance when either Ba²⁺ or Ca²⁺ ions were the charge carrier, an effect not observed with FPL 64176. BAY K 8644 enhanced the whole cell L-type channel Ca²⁺- or Ba²⁺-carried current without a change in deactivation tail kinetics. In contrast, enhancement by FPL 64176 was associated with a dramatic slowing of deactivation kinetics only when Ba²⁺ and not Ca²⁺ was the charge carrier. Current activation was slowed by FPL 64176 with either charge carrier, an effect arising from a clustering of agonist-modified long-duration openings toward the end of the voltage step. These data indicate that agonists enhanced L-type current by distinct mechanisms dependent on the permeant ion, indicating that care must be considered when used as diagnostic tools.

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