Neurotransmitter release from tottering mice nerve terminals with reduced expression of mutated P- and Q-type Ca2+-channels.
Neurotransmitter release is triggered by Ca2+-influx through multiple sub-types of high voltage-activated Ca2+-channels. Tottering mice have a mutation in the alpha1A pore-forming subunit of P- and Q-type Ca2+-channels, two prominent sub-types that regulate transmitter release from central nerve terminals. Immunoblotting analysis of purified forebrain terminals from tottering mice revealed an 85% reduction in the protein expression level of the mutated alpha1A subunit compared to expression of the alpha1A subunit in wild-type terminals. In contrast, the expression of the alpha1B subunit of the N-type Ca2+-channels was unchanged. Release of the amino acids glutamate and GABA and of the neuropeptide cholecystokinin (CCK) induced by a short (100 ms) depolarization pulse was unchanged in the terminals of tottering mice. Studies using specific blockers of Ca2+-channels however, revealed a reduced contribution of P- and Q-type Ca2+-channels to glutamate and cholecystokinin release, whereas a greater reliance on N-type Ca2+-channels for release of these transmitters was observed. In contrast, the contribution of the P-, Q- and N-type Ca2+-channels to the release of GABA was not altered in tottering mice. These results indicate that the expression of the alpha1A subunit was decreased in terminals from tottering mice, and that a decreased contribution of P- and Q-type Ca2+-channels to the release of glutamate and cholecystokinin was functionally compensated by an increased contribution of N-type Ca2+-channels.
Leenders
A G Miriam
AG
Swammerdam Institute for Life Sciences, Section Neurobiology, Faculty of Science, University of Amsterdam, Kruislaan 320, 1090 GB Amsterdam, The Netherlands.
van den Maagdenberg
Arn M J M
AM
Lopes da Silva
Fernando H
FH
Sheng
Zu-Hang
ZH
Molenaar
Peter C
PC
Ghijsen
Wim E J M
WE
D000818:Animals; D020865:Calcium Channels, P-Type / Q000096:biosynthesis* / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000096:biosynthesis* / Q000235:genetics*; D002766:Cholecystokinin / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D015151:Immunoblotting; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009411:Nerve Endings / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin