title: Sensitivity to voltage-independent inhibition determined by pore-lining region of the acetylcholine receptor.
abstract: 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.
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville 32610, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Francis
authors.forename: K I
authors.initials: KI
authors.lastname: Choi
authors.forename: B A
authors.initials: BA
authors.lastname: Horenstein
authors.forename: R L
authors.initials: RL
authors.lastname: Papke
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D003652:Decanoic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000502:physiology; D009474:Neurons / Q000502:physiology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D018075:RNA, Complementary; D051381:Rats; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D014982:Xenopus laevis
chemical_list: D003652:Decanoic Acids; D046911:Macromolecular Substances; D018733:Nicotinic Antagonists; D010880:Piperidines; D018075:RNA, Complementary; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; C083752:Tinuvin 770; D000109:Acetylcholine