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NIDA Proteomics Center
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Investigators
> Leonard K. Kaczmarek
Modulation of Slack and Slick
Channels by Protein Phosphorylation
Leonard K. Kaczmarek, Departments of Pharmacology and Cellular and Molecular
Physiology, Yale University
Potassium channels that are activated by
intracellular Na+ (KNa channels) are expressed at high levels in many brain
regions, including the amygdala and the striatum, suggesting that their activity
regulates the firing patterns of neurons in reward/addition pathways. These
channels regulate the rate at which neuronal firing adapts to maintained
stimulation. KNa channels are encoded by two genes, Slack and Slick.
In addition to being regulated by changes in intracellular Na+, both Slack and
Slick channels are very strongly modulated by the activation of protein kinase
C, and this enzyme represents the most potent mechanism currently known to
regulate these channel. Activation of protein kinase C increases Slack currents
and slows their rate of activation. In contrast to Slack channels, the activity
of Slick channels, as well as of Slack/Slick heteromeric channels, is strongly
suppressed upon activation of protein kinase C. A variety of experiment
approaches have indicated that the substrate sites that modulate channel
activity are likely to be on the very large cytoplasmic C-terminal domains of
the channel subunits themselves. These same C-terminal domains have been shown
to interact with proteins that regulate local protein translation in neurons,
suggesting that phosphorylation of the C-terminal domains may regulate the
interaction of these proteins with components of the local protein synthetic
machinery. Experiments in this project will use the Protein Post-Translational (PTM)
Identification & Profiling Core of the Center to identify the specific amino
acid residues at which the Slack and Slick channels are phosphorylated under
both basal conditions and after activation of protein kinase C. Combined with
electrophysiological and molecular biological approaches, this information will
lead to an understanding of the contribution of these channels to neuronal
firing patterns and to the modulation of synaptic transmission. |
