Modulation of single channels underlying hippocampal L-type current enhancement by agonists depends on the permeant ion.
The influx of calcium (Ca(2+)) ions through L-type channels underlies many cellular processes, ranging from initiation of gene transcription to activation of Ca(2+)-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 (Ba(2+)) was the permeant ion. BAY K 8644 increased single-channel conductance when either Ba(2+) or Ca(2+) ions were the charge carrier, an effect not observed with FPL 64176. BAY K 8644 enhanced the whole cell L-type channel Ca(2+)- or Ba(2+)-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 Ba(2+) and not Ca(2+) 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.
Tavalin
Steven J
SJ
Department of Pharmacology and MRC Centre for Synaptic Plasticity, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Shepherd
Dawn
D
Cloues
Robin K
RK
Bowden
Sarah E H
SE
Marrion
Neil V
NV
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D004553:Electric Conductivity; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D010539:Permeability; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D002120:Calcium Channel Agonists; D020746:Calcium Channels, L-Type; D011758:Pyrroles; C071658:FPL 64176; D001464:Barium; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium