Regulation of nicotinic acetylcholine receptor desensitization by Ca2+.
The relationship between the concentration of intracellular Ca2+ ([Ca2+](i)) and recovery from desensitization of nicotinic acetylcholine receptors (nAChRs) in rat medial habenula (MHb) neurons was investigated using the whole cell patch-clamp techniques in combination with microfluorescent [Ca2+](i) measurements. Recovery from desensitization was assessed with a paired-pulse agonist application protocol. Application of 100 microM nicotine (5 s) caused pronounced desensitization of nAChRs, after which recovery proceeded with two components. The relative weight of the two phases of recovery was sensitive to the nature of the intracellular Ca2+ chelator, with a greater fraction of channels recovering during the fast phase in the presence of BAPTA than EGTA. Recovery was affected by differential Ca2+ buffering only when Ca2+ was present in the extracellular solution, implying that Ca2+ influx through nAChRs was responsible for slowing the recovery. Simultaneous [Ca2+](i) measurements showed that recovery from desensitization was inversely correlated with the instantaneous [Ca2+](i), further supporting the suggestion that elevation of [Ca2+](i) limits the return of nAChRs to the resting state. In a separate set of experiments, activation of voltage-gated Ca2+ channels during the recovery phase produced a sufficiently large increase in [Ca2+](i) to reduce recovery from desensitization even in the absence of Ca2+ influx through nAChRs. Overall, it is suggested that Ca2+ entry through both nAChRs and voltage-gated Ca2+ channels exerts a negative feedback on nAChR activity through stabilization of desensitized states. The interaction of these two Ca2+ sources could form the basis of a coincidence detector under specific circumstances.
Guo
Xiaochuan
X
Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, 1825 University Boulevard, Birmingham AL 35294-2182, USA.
Lester
Robin A J
RA
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D005456:Fluorescent Dyes; D019262:Habenula / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D015220:Calcium Channels; D002614:Chelating Agents; D005456:Fluorescent Dyes; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D002118:Calcium