Obtaining a precise understanding of the mechanism(s) by which endogenous neuromodulators such as dopamine (DA) regulate glutamergic excitatory transmission could lead to better for patients afflicted with epilepsy, Parkinson's Disease, schizophrenia, and drug addiction. Activation of the D1 dopamine receptor subtype, in particular, modulates glutamate-induced neuronal excitability in frontal cortex, hippocampus and neostriatum. Little is known about molecular mechanism(s) by which D1 receptor signaling modulates excitatory transmission. We recently identified a single transmembrane protein designated Calcyon which interacts with D1 DA receptors and localizes to vesicles in dendritic spines. Via interaction with Calcyon, D1 receptors stimulate release of Ca++ from internal stores (Ca++i) in an activity-dependent manner in heterologous expression system. A similar activity-dependent, D1 receptor agonist stimulated response is detectable by Fura-2 Ca++ imaging of primary cultures of cortical and hippocampal neurons. Our overarching hypothesis is that Calcyon enhances D1 receptor signaling through Gq/11 by serving as a link connecting D1 receptors to IP3 regulated Ca++ stores. We will determine how D1 DA receptor signaling through Gq/11 is primed, and how Calcyon enhances D1 receptor-mediated IP3 signaling. Using Ca++ imaging and peptides to block the D1 receptor:Calcyon interaction, we will determine if Calcyon is required for D1 agonist stimulated Ca++i release in dendritic spines. We propose to identify other GPCRs and accessory proteins that interact with Calcyon by yeast two-hybrid and phage display screens. We will determine how these proteins are involved in regulating release of Ca++ from vesicular stores. The results of this research should provide insight into clinical strategies to selectively boost or dampen D1 receptor mediated neuromodulation of excitatory transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063271-02
Application #
6539241
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Asanuma, Chiiko
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$251,125
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Muthusamy, Nagendran; Chen, Yong-Jun; Yin, Dong-Min et al. (2015) Complementary roles of the neuron-enriched endosomal proteins NEEP21 and calcyon in neuronal vesicle trafficking. J Neurochem 132:20-31
Xiao, Jiping; Bergson, Clare (2013) Detection of cell surface dopamine receptors. Methods Mol Biol 964:3-13
Muthusamy, Nagendran; Faundez, Victor; Bergson, Clare (2012) Calcyon, a mammalian specific NEEP21 family member, interacts with adaptor protein complex 3 (AP-3) and regulates targeting of AP-3 cargoes. J Neurochem 123:60-72
Vazdarjanova, A; Bunting, K; Muthusamy, N et al. (2011) Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood. Mol Psychiatry 16:672-84
Davidson, Heather Trantham; Xiao, Jiping; Dai, Rujuan et al. (2009) Calcyon is necessary for activity-dependent AMPA receptor internalization and LTD in CA1 neurons of hippocampus. Eur J Neurosci 29:42-54
Muthusamy, Nagendran; Ahmed, Sanaa A; Rana, Brinda K et al. (2009) Phylogenetic analysis of the NEEP21/calcyon/P19 family of endocytic proteins: evidence for functional evolution in the vertebrate CNS. J Mol Evol 69:319-32
Dai, Rujuan; Ali, Mohammad K; Lezcano, Nelson et al. (2008) A crucial role for cAMP and protein kinase A in D1 dopamine receptor regulated intracellular calcium transients. Neurosignals 16:112-23
Negyessy, Laszlo; Bergson, Clare; Garab, Sandor et al. (2008) Ultrastructural localization of calcyon in the primate cortico-basal ganglia-thalamocortical loop. Neurosci Lett 440:59-62
Xiao, Jiping; Dai, Rujuan; Negyessy, Laszlo et al. (2006) Calcyon, a novel partner of clathrin light chain, stimulates clathrin-mediated endocytosis. J Biol Chem 281:15182-93
Bergson, Clare; Levenson, Robert; Goldman-Rakic, Patricia S et al. (2003) Dopamine receptor-interacting proteins: the Ca(2+) connection in dopamine signaling. Trends Pharmacol Sci 24:486-92

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