The intrinsic excitability of mammalian neurons reflects the complex interplay between the inward and outward membrane conductances that underlie each neuron’s unique electrical activity pattern, and are governed by the expression, localization and activity of voltage-gated ion channels. These processes are homeostatically regulated during development and aging, and in response to short- and long-term changes in neuronal activity in the face of alteratered synaptic stimulations, which otherwise could drive the neuronal activity towards extreme excitation or quiescence. Altered expression and/or modulation of localization and function of voltage-gated sodium (Nav) and potassium (Kv) channels mediate these homeostatic processes in response to altered neuronal activity and nerumodulations.

Increase in the intracellular Ca 2+ concentrations in neurons as a result of altered neuronal activity or neuromodulations, lead to the activation of a variety of protein kinases and phosphatases, which modify the phosphorylation state of a large variety of neuronal proteins including ion channels. These post-translational modifications often alter the localization and/or voltage-dependent biophysical properties of ion channel proteins. Since Kv channels are the key regulatory components of membrane excitability in neurons, modulation of their functional properties by post-translational modifications play a critical role in the regulation of intrinsic excitability during altered neuronal activity and neuromodulations.

We have recently shown that robust and sustained increase in the intracellular Ca 2+ levels, and subsequent activation of the protein phosphatase calcineurin in mammalian central neurons in response to increased excitatory activity, epileptic seizures, and cholinergic neuromodulations, leads to rapid dephosphorylation of the major somatodendritic delayed rectifier Kv channel Kv2.1. Dephosphorylation of Kv2.1 leads to redistribution channel localization and alterations in the voltage-dependent gating properties of neuronal delayed rectifier K + currents, which plays a neuroprotective role by suppressing the neuronal firing frequency under conditions of altered excitability.

We are interested in studying how the membrane excitability in mammalian central neurons are intrinsically regulated by modulation of localization & function of different Kv channels in response to diverse neuromodulatory stimuli acting through specific G-protein coupled receptor (GPCR)-mediated intracellular signaling pathways.

We are also interested in studying molecular organization, activity-dependent modulation and regulation of trafficking, localization, and functional properties of Kv & thermo-TRP channels and their signaling complexes in sensory neurons, in response to diverse pain-producing chemical, thermal, and mechanical stimuli.

We combine upto-date molecular/cell biological, biochemical, proteomic, fluorescence immunocyto-/histochemical, confocal imaging, and electrophysiological methods to answer these questions. These studies will certainly contribute significantly to the development of therapeutic interventions for a number of neuronal disorders like epilepsies, ischemia, and neuropathic pain.

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