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J Neurophysiol (March 31, 2004). doi:10.1152/jn.00700.2003
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Submitted on July 21, 2003
Accepted on March 29, 2004

Modulation of single channels underlying hippocampal L-type current enhancement by agonists depends on the permeant ion

Steven J. Tavalin1, Dawn Shepherd2, Robin K. Cloues3, Sarah E. Bowden2, and Neil V. Marrion2*

1 Pharmacology, University of Tennessee, Memphis, TN, USA
2 Pharmacology, University of Bristol, Bristol, United Kingdom
3 Pharmacology, Univ. of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: N.V.Marrion{at}bris.ac.uk.

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 towards 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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