Francis, MM Choi, KI Horenstein, BA Papke, RL 2024-01-21T17:09:04Z 2024-01-21T17:09:04Z 2021-09-01 1998-05 0006-3495 https://pubs.kist.re.kr/handle/201004/143115 Some noncompetitive inhibitors (e.g., ganglionic blockers) exhibit selectivity for the inhibition of neuronal nicotinic acetylcholine receptors (nAChRs). This study characterizes the mechanism of selective long-term inhibition of neuronal and muscle-neuronal chimeric nAChRs by bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (bis-TMP-10 or BTMPS), a bifunctional form of the potent ganglionic blocker tetramethylpiperidine. Long-term inhibition of neuronal nAChRs by bis-TMP-10 has been previously demonstrated to arise, at least in part, from the binding of the bis compound to neuronal beta-subunits. In this study, long-term inhibition is demonstrated to be dependent upon the presence of sequence element(s) within the pore-lining second transmembrane domain (tm2) of neuronal beta-subunits; however, the inhibitor binding site itself does not appear to be contained within the segment of the channel pore influenced by the membrane electric field. Specifically, our results imply that bis-TMP-10 interacts with an activation-sensitive element, the availability of which may be regulated by a sequence in the tm2 domain. Furthermore, we demonstrate a compound length requirement for long-term inhibition that would be consistent with binding to multiple sites located on the extracellular portion of the receptor. English BIOPHYSICAL SOCIETY AFFINITY BINDING-SITE NONCOMPETITIVE ANTAGONIST TORPEDO-CALIFORNICA NICOTINIC RECEPTOR H-3 CHLORPROMAZINE KINETIC-PROPERTIES XENOPUS OOCYTES ALPHA-SUBUNIT ION CHANNEL CURRENTS Sensitivity to voltage-independent inhibition determined by pore-lining region of the acetylcholine receptor Article 10.1016/S0006-3495(98)77940-8 1 BIOPHYSICAL JOURNAL, v.74, no.5, pp.2306 - 2317 BIOPHYSICAL JOURNAL 74 5 2306 2317 scie scopus 000073429700019 2-s2.0-0344701102 Biophysics Biophysics Article AFFINITY BINDING-SITE NONCOMPETITIVE ANTAGONIST TORPEDO-CALIFORNICA NICOTINIC RECEPTOR H-3 CHLORPROMAZINE KINETIC-PROPERTIES XENOPUS OOCYTES ALPHA-SUBUNIT ION CHANNEL CURRENTS acetylcholine