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Functional Regulation of T-Type Calcium Channels by S-Nitrosothiols in the Rat Thalamus

¹Department of Anesthesiology, ²Pediatric Critical Care, and ³Neuroscience Graduate Program, University of Virginia Health System, School of Medicine, Charlottesville, Virginia

Submitted 31 August 2006; accepted in final form 29 January 2007

Although T-type Ca²⁺ channels in the reticular thalamic nucleus (nRT) have a central function in tuning neuronal excitability and are implicated in sensory processing, sleep, and epilepsy, the mechanisms involved in their regulation are poorly understood. Here we recorded T-type Ca²⁺ currents from intact nRT neurons in brain slices from young rats and investigated the mechanisms of T-type channel modulation by S-nitrosothiols (SNOs). We found that extracellular application of S-nitrosoglutathione (GSNO), S-nitrosocysteine (CSNO) and S-nitroso-N-acetyl-penicillamin (SNAP) rapidly and reversibly reduced T-type currents. The effects of SNOs are strongly stereoselective at physiological concentrations: _L-CSNO was fourfold more effective in inhibiting T-type current than was _D-CSNO. The effects of GSNO were abolished if cells had been treated with free hemoglobin or N-ethylmaleimide, an irreversible alkylating agent but not by 8-bromoguanosine-3',5'-cyclomonophosphate sodium salt, a membrane-permeant cGMP analogue or 1H-(1,2,4) oxadiazolo (4,3-a) quinoxalin-1-one, a specific soluble guanylyl cyclase inhibitor. In addition, bath applications of GSNO inhibited T-type currents in nucleated outside-out patches and whole cell recordings to a similar extent, with minimal effect on cell-attached recordings, suggesting a direct effect of GSNO on putative extracellular thiol residues on T-type channels. Biophysical studies indicate that GSNO decreased the availability of T-type channels at physiological potentials by modifying gating and stabilizing inactive states of the channels. In current-clamp experiments, GSNO diminished the amplitude of low-threshold calcium spikes and frequency of spike firing with minimal effects on the passive membrane properties. Collectively, the results indicate that SNOs may be a class of endogenous agents that control the functional states of the thalamus.

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