[Modulation of excitability in midbrain dopaminergic neurons and skeletal muscles by neuronal nicotinic receptors: perspectives from knockout mice].
Neuronal nicotinic receptors (nAChRs) are widely expressed in the central and peripheral nervous systems, and also found in several non-neuronal tissues, including skeletal muscles. Since neuronal nAChRs possess a high Ca2+ permeability, we investigated the mechanisms of intracellular Ca2+ mobilization through nAChR in midbrain dopaminergic neurons and skeletal muscles, using alpha 7-/- or beta 2-/- mice. RT-PCR study showed the existence of alpha 7 mRNA in denervated muscles of wild-type mice. Choline (alpha 7 agonist) elicited a muscle depolarization, but this component was abolished in alpha 7-/- mice. These suggest that alpha 7-nAChR up-regulated in denervated muscle may contribute to regeneration of the damaged neuromuscular synapse. Moreover, fura-2-imaging analyses in midbrain slices demonstrated that nicotine-elicited Ca2+ mobilization was diminished in beta 2-/- mice. The Ca2+ mobilization was markedly inhibited by dantrolene. Therefore, the Ca2+ influx due to beta 2-nAChR activation appears to be amplified by the recruitment of intracellular Ca2+ stores. To regulate unusual nAChR functions in neurological diseases, the search for new and selective ligands has continuously increased. We examined the effects of frog alkaloids on nAChRs expressed in Xenopus oocytes, and found that indolizidines 235B' selectively blocked alpha 4 beta 2-nAChR. Thus, the approach based on natural products can still provide a great advantage for producing novel therapeutics.
Tsuneki
Hiroshi
H
Department of Clinical Pharmacology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan.
Kimura
Ikuko
I
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000032:analysis*; D007212:Indolizines / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000032:analysis / Q000502:physiology*; D014981:Xenopus
D007212:Indolizines; D011978:Receptors, Nicotinic; C035094:indolizine; D002118:Calcium; D004298:Dopamine