title: Presynaptic Ca(2+) influx at a mouse central synapse with Ca(2+) channel subunit mutations.
abstract: Genetic alterations in Ca(2+) channel subunits can be used to study the interaction among channel subunits and their roles in channel function. P/Q- and N-type Ca(2+) channels reside at the presynaptic terminal and control the release of neurotransmitter at mammalian central synapses. We used fluorescence imaging techniques to investigate presynaptic Ca(2+) currents and neurotransmitter release at hippocampal Schaffer collateral synapses in both tottering (tg, alpha(1A) subunit) and lethargic (lh, beta(4) subunit) mutant mice. Application of selective toxins revealed a large reduction in presynaptic P/Q-type Ca(2+) transients, from 39% of total in +/+ mice to 6% in tg/tg mice, whereas the proportion of N-type increased from 35 to 68%, respectively. Neurotransmitter release in the tg/tg mutant relied almost exclusively on N-type channels, as shown by the complete blockade of synaptic transmission with omega-conotoxin GVIA. Remarkably, loss of beta4, a subunit predicted to regulate the subcellular targeting and modulation of both P/Q- and N-type channels, resulted in no significant difference in the ratio of Ca(2+) channel subtypes or Ca(2+) dependence of neurotransmitter release in lethargic mice. G-protein-mediated inhibition of Ca(2+) channels was also unaltered. These results indicate that a profound decrease in presynaptic P/Q-type currents leads to dependence of neurotransmitter release on N-type channels. In contrast, absence of beta(4) appears not to compromise either P/Q- or N-type channel function at this hippocampal synapse, implicating rescue of presynaptic Ca(2+) currents by other available beta subunits. The present study reveals compensatory molecular mechanisms in the regulation of presynaptic Ca(2+) entry and neurotransmitter release.
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qian
authors.forename: J L
authors.initials: JL
authors.lastname: Noebels
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism*; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D015763:2-Amino-5-phosphonovalerate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000241:Adenosine; D001418:Baclofen; D002118:Calcium; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D009419:Nerve Tissue Proteins; D020866:omega-Conotoxin GVIA; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC