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Synaptic transmission
and plasticity: Role of the ClC-3 Cl- channel |
Secretory
granules maintain a low intragranular pH and it is becoming increasingly
recognized that this phenomenon is important to secretion. Cl- entry
across the granule membrane is thought to be required to shunt H influx via the
V-ATPase, thus preventing the build-up of a large transgranular membrane
potential. We have shown, for the first time in pancreatic beta cells, that
chloride channels (specifically ClC-3) play a role in insulin secretion, likely
through regulation of acidification. Our preliminary data utilizing ClC-3
knock-out mice indicate that beta-cells are defective in exocytosis and the
mutant animals exhibit aberrant glucose tolerance. The goal of the present
application is to determine the importance of this phenomenon to insulin
secretion, understand its mechanism and determine the gating processes that
lead to activation of the channel.
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The excitatory glutamatergic synapse
in hippocampal neurons is the best described interface between electrical
activity and memory encoding in the central nervous system. We have found that
ClC-3 chloride channels localize to the post-synaptic plasma membranes of
hippocampal neurons where they are both spatially and functionally linked to
excitatory glutamatergic receptors. Synaptic
development and plasticity are integral to our understanding of neuronal
function and disease, so understanding the events that underlie these
processes, including the role of ClC-3 chloride channels, is of fundamental
significance. Our proposed studies are
targeted at an integrated understanding of the role postsynaptically expressed
ClC-3 plays in the fundamental aspects of hippocampal neuronal excitability as
well as synaptic plasticity.
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The role of Cl- channels in sculpting the innate immune response |
Secretion
of stored secretory products and related organelles is important for immune
system function. We are exploring the
role of the Cl- channel CFTR in acidifying and priming secretory
vesicles for secretion, thereby, providing yet another limb to the network of
regulatory factors controlling secretion in the mononuclear phagocyte family
which includes the antimicrobial macrophage cells. Chloride
channels in lung macrophages may be a new therapeutic target in the
treatment of chronic lung inflammation in diseases like cystic fibrosis, COPD
and asthma.
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