title: Iptakalim inhibits nicotinic acetylcholine receptor-mediated currents in dopamine neurons acutely dissociated from rat substantia nigra pars compacta.
abstract: Iptakalim hydrochloride, a novel cardiovascular ATP-sensitive K(+) (K(ATP)) channel opener, has shown remarkable antihypertensive and neuroprotective effects in a variety of studies using in vivo and in vitro preparations. We recently found that iptakalim blocked human alpha4-containing nicotinic acetylcholine receptors (nAChRs) heterologously expressed in the human SH-EP1 cell line. In the present study, we examined the effects of iptakalim on several neurotransmitter-induced current responses in single DA neurons freshly dissociated from rat substantia nigra pars compacta (SNc), using perforated patch-clamp recordings combined with a U-tube rapid drug application. In identified DA neurons under voltage-clamp configuration, glutamate-, NMDA-, and GABA-induced currents were insensitive to co-application with iptakalim (100 microM), while whole-cell currents induced by ACh (1 mM+1 microM atropine) or an alpha4beta2 nicotinic acetylcholine receptors relatively selective agonist, RJR-2403 (300 microM), were eliminated by iptakalim. Iptakalim inhibited RJR-2403-induced current in a concentration-dependent manner, and reduced maximal RJR-2403-induced currents at the highest agonist concentration, suggesting a non-competitive block. In current-clamp mode, iptakalim failed to affect resting membrane potential and spontaneous action potential firing, but abolished RJR-2403-induced neuronal firing acceleration. Together, these results indicate that in dissociated SNc DA neurons, alpha4-containing nAChRs, rather than ionotropic glutamate receptors, GABA(A) receptors or perhaps K-ATP channels are the sensitive targets to mediate iptakalim's pharmacological roles.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: DeChon
authors.forename: K C
authors.initials: KC
authors.lastname: Yan
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Hu
authors.forename: J
authors.initials: J
authors.lastname: Wu
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009538:Nicotine / Q000031:analogs & derivatives / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000166:cytology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018377:Neurotransmitter Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011437:Propylamines; D011978:Receptors, Nicotinic; D018698:Glutamic Acid; C012419:metanicotine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D009538:Nicotine; D000109:Acetylcholine; D004298:Dopamine