Somatic Ca(2+) dynamics in response to choline-mediated excitation in histaminergic tuberomammillary neurons.
Histaminergic tuberomammillary (TM) neurons of the posterior hypothalamus have been implicated in cognition, alertness and sleep-wakefulness cycles. Spontaneous firing of TM neurons has been associated with histamine release and wakefulness. The expression of alpha7 nicotinic acetylcholine receptors (nAChRs) in TM neurons suggests a role for endogenous choline and for nicotinic drugs in the regulation of intracellular Ca(2+) metabolism, normal TM neuronal activity and histamine release. First, we established the link between TM neuronal spontaneous firing frequency and cytosolic free Ca(2+) concentration ([Ca(2+)](i)). A strong correlation was observed: an onset of spontaneous firing (3-4Hz) was accompanied by a 20-fold increase in [Ca(2+)](i) from 56+/-18 nM to 1.0+/-0.6 microM. The same range of firing frequencies has been observed in TM neurons in vivo and is associated with wakefulness. Secondly, choline-induced activation of alpha7 nAChRs did not elevate [Ca(2+)](i) directly, i.e. in the absence of high-threshold voltage-gated Ca(2+) channel (HVGCC) activation. Cd(2+) (200 microM) completely blocked all Ca(2+) signals, but inhibited only 37+/-16% of alpha7 nAChR-mediated currents. Thirdly, the responsiveness of [Ca(2+)](i) to choline-mediated excitation was inhibited by hyperpolarization and enhanced by depolarization, sensitizing [Ca(2+)](i) at membrane voltages associated with normal TM neuronal activity. These properties of [Ca(2+)](i) define the ability of TM neurons to translate cholinergic stimuli of identical strengths into different cytosolic Ca(2+) effects, providing the physiological substrate for state-specific modulation of incoming cholinergic information and would be expected to play a very important role in determining activity profiles of TM neurons exposed to elevated concentrations of cholinergic agents, such as choline and nicotine.
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Department of Pharmacology and Therapeutics, University of Florida, Box 100267 JHMHSC, SW 1600 Archer Road, Gainesville, Florida 32610-0267, USA. vuteshev@utmem.edu
Knot
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D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002794:Choline / Q000494:pharmacology*; D004558:Electric Stimulation / Q000379:methods; D006632:Histamine / Q000378:metabolism*; D007026:Hypothalamic Area, Lateral / Q000166:cytology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D018697:Nootropic Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D014851:Wakefulness
D018697:Nootropic Agents; D002104:Cadmium; D006632:Histamine; D002794:Choline; D002118:Calcium