P/Q-type Ca currents conducted by Cav2.1 channels are responsible for the Ca entry that initiates neurotransmitter release at most fast glutamatergic synapses. Ca entering through presynaptic Ca channels forms a local domain of high Ca concentration that activates exocytosis in the near vicinity. Therefore, synaptic vesicles must dock near presynaptic Ca channels to be efficiently released. Neurotransmitter release is dependent on the third or fourth power of the Ca current through the presynaptic Ca channels, so small changes in Ca entry have large effects on synaptic transmission. Ca-dependent facilitation and depression of synaptic transmission is an important determinant of information coding and transmission in the nervous system. Our results in the present project period have given important new insights into the function and regulation of presynaptic Ca channels in synaptic transmission and short-term synaptic plasticity. First, we have further defined the molecular mechanism for interaction of Ca channels with SNARE proteins and the regulation of that interaction by protein phosphorylation. Second, we have shown that the calmodulin-like neuronal Ca sensor (nCaS) protein VILIP-2 regulates Cav2.1 channels by interaction at the same binding site as calmodulin and CaBP1, but has a distinct set of regulatory effects. Third, we have found that N-terminal myristoylation is required for the distinct regulatory effects of CaBP1 and VILIP-2 on Cav2.1 channels and that the N-terminal lobe of these nCaS proteins confers their specificity of regulation. Fourth, we have discovered that nCaS-dependent facilitation and inactivation of Cav2.1 channels is primarily responsible for short-term facilitation and depression of synaptic transmission in transfected superior cervical ganglion (SCG) neuron synapses, providing the first insight into the molecular mechanisms responsible for short-term synaptic plasticity. Finally, we have found unexpectedly that Ca/calmodulin-dependent protein kinase II (CaMKII) regulates Cav2.1 channels by specific binding to a site on the C-terminal domain, potentially positioning the kinase for rapid response to Ca entry and phosphorylation of nearby proteins. In the next project period, we plan to build on these important advances to: 1. further define the molecular mechanisms of binding and regulation of Cav2.1 channels by nCaS proteins;2. determine the functions of nCaS proteins in short-term synaptic plasticity;3. explore the signaling functions of CaMKII specifically bound to Cav2.1 channels;and 4. determine the functional role of presynaptic CaMKII in synaptic transmission and synaptic plasticity. These experiments will provide novel insights into the regulation of presynaptic Ca channels and the role of this regulation in short-term synaptic plasticity, an essential form of information encoding and transmission in the nervous system.

Public Health Relevance

Calcium channels in nerve terminals begin the process of synaptic transmission, which communicates information from one nerve to cell to another as well as to muscle and hormone-secreting cells. Failure of correct function and regulation of these calcium channels contributes to epilepsy, migraine, ataxia, and other neurological diseases. Our proposed research will provide novel insights into the regulation of these presynaptic calcium channels and their function in short-term synaptic plasticity, an essential process for normal coding and transmission of information in the nervous system and a target for neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022625-26
Application #
8115018
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
1985-09-09
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
26
Fiscal Year
2011
Total Cost
$334,425
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Nanou, Evanthia; Scheuer, Todd; Catterall, William A (2016) Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to long-term potentiation and spatial learning. Proc Natl Acad Sci U S A 113:13209-13214
Nanou, Evanthia; Yan, Jin; Whitehead, Nicholas P et al. (2016) Altered short-term synaptic plasticity and reduced muscle strength in mice with impaired regulation of presynaptic CaV2.1 Ca2+ channels. Proc Natl Acad Sci U S A 113:1068-73
Nanou, Evanthia; Sullivan, Jane M; Scheuer, Todd et al. (2016) Calcium sensor regulation of the CaV2.1 Ca2+ channel contributes to short-term synaptic plasticity in hippocampal neurons. Proc Natl Acad Sci U S A 113:1062-7
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