Tetraethylammonium potentiates the activity of muscarinic potassium channels in guinea-pig atrial myocytes.
The modulation of native muscarinic potassium channels (KACh) by tetraethylammonium (TEA) was studied at 35 degrees C in cell-free patches from acutely dissociated guinea-pig atrial myocytes. The channels were identified unambiguously by their conductance, inward rectification, rapid gating kinetics and pharmacological responses to muscarinic agonists and GTPgammaS. Addition of 5 mM TEA to the cytoplasmic side of the patches almost doubled the open probability of KACh channels that had been activated maximally by GTPgammaS. In contrast even 30 mM TEA did not significantly potentiate the response to carbachol in whole-cell recordings. Unlike GTPgammaS, TEA alone did not activate KACh channels de novo, but in patches that showed spontaneous KACh activity, 5 mM TEA increased channel open probability fourfold in the absence of added sodium, ATP or guanine nucleotides. Furthermore, the effect of TEA was not blocked by 10 uM atropine or by 1 mM GDPbetaS, and subsequent addition of 0.1 mM GTPgammaS did not stimulate channel activity further in the presence of TEA. Phosphatidylinositol 4,5-bisphosphate (PIP2) also stimulates KACh channels under these conditions, but the kinetics of gating differ from channels stimulated by either TEA or GTP, which are very similar to one another. The effects of TEA were not mimicked by tetramethyl- or tetrapentylammonium or by sodium or spermine, and TEA did not potentiate the activity of other inwardly rectifying potassium (KATP) channels in patches from cardiac myocytes. We consider the possibility that TEA is mimicking the effect of an unidentified cellular factor, not sodium or PIP2, which normally occupies the TEA site on KACh channel proteins but which diffuses away when the patch is excised.
Wang
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Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Armstrong
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D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology*
D018679:Cholinergic Agonists; D015221:Potassium Channels; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019789:Tetraethylammonium; D002217:Carbachol; D000109:Acetylcholine