Voltage-gated calcium (Ca2+) channels play a central role in neuronal function and are essential for converting electrical activity into biochemical events. The main goal of this proposal is to identify the molecular mechanisms by which voltage-gated calcium channels activate signaling cascades that mediate gene expression and promote neuronal survival. Neurons and muscle cells express at least ten different kinds of voltage-gated calcium channels that vary in their subcellular localization and biophysical properties. L-type channels (LTCs) are particularly effective at activating transcriptional pathways and at promoting neuronal survival. The transcription factors CREB and MEF-2 are two important targets of LTC signaling that regulate differentiation and plasticity in the nervous system. The biophysical and biochemical features that allow LTCs to activate gene expression and suppress apoptosis are not well understood. To address the question of how LTCs are linked to signaling pathways the following specific aims are proposed: 1) To determine the structural and biophysical features that allow L-type calcium channels to activate transcription. 2) To determine whether specific L-type channel interacting proteins link the channel to signaling pathways that lead to the activation of transcription. 3) To determine what features of L-type calcium channels allow them to inhibit neuronal apoptosis and promote survival. Biochemical, cell biological and electrophysiological techniques will be used to develop these specific aims. We have recently developed a method of using dihydropyridine insensitive LTCs to investigate LTC signaling in primary neurons and we plan to use this approach for these studies. We have also identified several LTC-interacting proteins that may be important for channel regulation and signaling and we plan to investigate their importance for signaling to the nucleus. The results of these experiments will provide critical insights into how voltage-gated channels activate the signaling pathways that regulate the structure and function of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048564-03
Application #
7014571
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2004-02-15
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$286,817
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Tsuruta, Fuminori; Dolmetsch, Ricardo E (2015) PIKfyve mediates the motility of late endosomes and lysosomes in neuronal dendrites. Neurosci Lett 605:18-23
Gomez-Ospina, Natalia; Panagiotakos, Georgia; Portmann, Thomas et al. (2013) A promoter in the coding region of the calcium channel gene CACNA1C generates the transcription factor CCAT. PLoS One 8:e60526
Park, Chan Young; Shcheglovitov, Aleksandr; Dolmetsch, Ricardo (2010) The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. Science 330:101-5
Park, Chan Young; Hoover, Paul J; Mullins, Franklin M et al. (2009) STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136:876-90
Tsuruta, Fuminori; Green, Eric M; Rousset, Matthieu et al. (2009) PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death. J Cell Biol 187:279-94
Mullins, Franklin M; Park, Chan Young; Dolmetsch, Ricardo E et al. (2009) STIM1 and calmodulin interact with Orai1 to induce Ca2+-dependent inactivation of CRAC channels. Proc Natl Acad Sci U S A 106:15495-500
Green, Eric M; Barrett, Curtis F; Bultynck, Geert et al. (2007) The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2. Neuron 55:615-32
Brenner, Jacob S; Dolmetsch, Ricardo E (2007) TrpC3 regulates hypertrophy-associated gene expression without affecting myocyte beating or cell size. PLoS One 2:e802
Krey, Jocelyn F; Dolmetsch, Ricardo E (2007) Molecular mechanisms of autism: a possible role for Ca2+ signaling. Curr Opin Neurobiol 17:112-9
Gomez-Ospina, Natalia; Tsuruta, Fuminori; Barreto-Chang, Odmara et al. (2006) The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell 127:591-606