Synaptic transmission is responsible for information transfer between neurons and its regulation underlies learning, memory, and many aspects of physiological regulation. N-type and P/Q-type Ca currents through Cav2.1 and Cav2.2 channels, respectively, are responsible for the Ca entry that initiates neurotransmitter release at most conventional fast 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 presynaptic Ca channels, so small changes in Ca entry have large effects on synaptic transmission. Synaptic plasticity due to Ca-dependent facilitation and inactivation of synaptic transmission is an important determinant of information coding and transmission. Many neurotransmitters that act through G protein-coupled receptors can inhibit the activity of presynaptic Ca channels and thereby inhibit synaptic transmission. Their inhibition is relieved by strong depolarization or by phosphorylation by protein kinase C. Our results in the present project period have given important new insights into regulation of presynaptic Ca channels by G proteins. We have analyzed the structure-function relationships of SNARE protein binding and its regulation at the synaptic protein interaction site, and we have shown that this site is necessary for reconstitution of synaptic transmission by exogenously expressed Ca channels. In addition, we have discovered a novel mechanism of Ca channel regulation by calmodulin and neuro-specific Ca binding proteins, which are likely to have important roles in short-term synaptic plasticity. In the next project period, we plan to build on these advances to further define the molecular mechanism of Ca channel function and regulation in synaptic transmission. We will determine the sites and mechanisms of action and the diversity of regulation of Cav2.1 channels by neuro-specific calmodulin (CaM)-Iike Ca binding proteins. We will further define the site of interaction of SNARE proteins with the synaptic protein interaction site of Cav2.1 channels and the regulation of SNARE protein binding and Cav2.1 channel function by phosphorylation by protein kinase C (PKC) and Ca/CaM-dependent protein kinase II (CaMKII). Based on this molecular information, we will analyze the functional significance of neuro-specific Ca binding proteins, SNARE proteins, and protein phosphorylation in regulation of synaptic transmission neurons in cell culture. Finally, we will probe the convergent regulation of Cav2.1 channel function and synaptic transmission by Ca-binding proteins, SNARE proteins, and protein phosphorylation. These studies will give important new insight into the mechanism and regulation of synaptic transmission and will further define the function of Cav2.1 channels and their regulation in synaptic plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022625-20
Application #
6897870
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
1985-09-09
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
20
Fiscal Year
2005
Total Cost
$350,575
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Nanou, Evanthia; Lee, Amy; Catterall, William A (2018) Control of Excitation/Inhibition Balance in a Hippocampal Circuit by Calcium Sensor Protein Regulation of Presynaptic Calcium Channels. J Neurosci 38:4430-4440
Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L et al. (2017) Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the ?2-adrenergic receptor in neurons. Sci Signal 10:
Patriarchi, Tommaso; Qian, Hai; Di Biase, Valentina et al. (2016) Phosphorylation of Cav1.2 on S1928 uncouples the L-type Ca2+ channel from the ?2 adrenergic receptor. EMBO J 35:1330-45
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
Tang, Lin; Gamal El-Din, Tamer M; Swanson, Teresa M et al. (2016) Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs. Nature 537:117-121
Southan, Christopher; Sharman, Joanna L; Benson, Helen E et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res 44:D1054-68
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
Catterall, William A (2015) Finding Channels. J Biol Chem 290:28357-73
Yan, Jin; Leal, Karina; Magupalli, Venkat G et al. (2014) Modulation of CaV2.1 channels by neuronal calcium sensor-1 induces short-term synaptic facilitation. Mol Cell Neurosci 63:124-31

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