The Role of Calcyon in Synaptic Integration

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date4/1/013/31/06

ASJC

  • Medicine(all)