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1 Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, United States; Vision Science Graduate Program, University of Alabama at Birmingham, Birmingham, Alabama, United States; McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, United States
2 Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, United States; Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama, United States; McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama, United States
* To whom correspondence should be addressed. E-mail: rlester{at}nrc.uab.edu.
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 microfluoresecent [Ca2+]i measurements. Recovery from desensitization was assessed with a paired-pulse agonist application protocol. Application of 100 µM nicotine (5 s) caused pronounced desensitization of nAChRs following 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 only affected by differential Ca2+ buffering when Ca2+ was present in the extracellular solution, implying that Ca2+ influx through nAChRs was responsible for slowing the recovery. In addition, 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 large enough 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 exert 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.
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