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NEUROPHARMACOLOGY

Acetylcholine Release at Neuromuscular Junctions of Adult Tottering Mice Is Controlled by N-(Ca_v2.2) and R-Type (Ca_v2.3) but Not L-Type (Ca_v1.2) Ca²⁺ Channels

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

The mutation in the _1A subunit gene of the P/Q-type (Ca_v2.1) Ca²⁺ channel present in tottering (tg) mice causes ataxia and motor seizures that resemble absence epilepsy in humans. P/Q-type Ca²⁺channels are primarily involved in acetylcholine (ACh) release at mammalian neuromuscular junctions. Unmasking of L-type (Ca_v1.1–1.2) Ca²⁺ channels occurs in cerebellar Purkinje cells of tg mice. However, whether L-type Ca²⁺ channels are also up-regulated at neuromuscular junctions of tg mice is unknown. We characterized thoroughly the pharmacological sensitivity of the Ca²⁺ channels, which control ACh release at adult tg neuromuscular junctions. Block of N- and R-type (Ca_v2.2–2.3), but not L-type Ca²⁺ channels, significantly reduced quantal content of end-plate potentials in tg preparations. Neither resting nor KCl-evoked miniature end-plate potential frequency differed significantly between tg and wild type (WT). Immunolabeling of Ca²⁺ channel subunits _1A, _1B, _1C, and _1E revealed an apparent increase of _1B, and _1E staining, at tg but not WT neuromuscular junctions. This presumably compensates for the deficit of P/Q-type Ca²⁺channels, which localized presynaptically at WT neuromuscular junctions. No _1C subunits juxtaposed with pre- or postsynaptic markers at either WT or tg neuromuscular junctions. Thus, in adult tg mice, immunocytochemical and electrophysiological data indicate that N- and R-type channels both assume control of ACh release at motor nerve terminals. Recruitment of alternate subtypes of Ca²⁺ channels to control transmitter release seems to represent a commonly occurring method of neuronal plasticity. However, it is unclear which conditions underlie recruitment of Ca_v2 as opposed to Ca_v1-type Ca²⁺ channels.

Address correspondence to: Dr. William D. Atchison, Department of Pharmacology and Toxicology, Michigan State University, B-331 Life Sciences Bldg., East Lansing, MI 48824-1317. E-mail: atchiso1{at}msu.edu