The Journal of Neurophysiology Vol. 81 No. 1 January 1999, pp. 225-233
Copyright ©1999 The American Physiological Society

Norepinephrine Inhibits a Toxin Resistant Ca²⁺ Current in Carotid Body Glomus Cells: Evidence for a Direct G Protein Mechanism

Jeffrey L. Overholt and Nanduri R. Prabhakar

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970

Overholt, Jeffrey L. and Nanduri R. Prabhakar. Norepinephrine inhibits a toxin resistant Ca²⁺ current in carotid body glomus cells: evidence for a direct G protein mechanism. J. Neurophysiol. 81: 225-233, 1999. Previous studies have demonstrated that endogenous norepinephrine (NE) inhibits carotid body (CB) sensory discharge, and the cellular actions of NE have been associated with inhibition of Ca²⁺ current in glomus cells. The purpose of the present study was to elucidate the characteristics and mechanism of NE inhibition of whole cell Ca²⁺ current isolated from rabbit CB glomus cells and to determine the type(s) of Ca²⁺ channel involved. NE (10 µM) inhibited 24 ± 2% (SE) of the macroscopic Ca²⁺ current measured at the end of a 25 ms pulse to 0 mV and slowed activation of the current. The ₂ adrenergic receptor antagonist, SK&F 86466, attenuated these effects. Inhibition by NE was fast and voltage-dependent i.e., maximal at 10 mV and then diminished with stronger depolarizations. This is characteristic of G protein subunit interaction with the ₁ subunit of certain Ca²⁺ channels, which can be relieved by depolarizing steps. A depolarizing step (30 ms to +80 mV) significantly increased (14 ± 1%) current in the presence of NE, whereas it had no effect before application of NE (1 ± 1%). To further test for the involvement of G proteins, NE was applied to cells where intracellular GTP was replaced by GDP-S. NE had little or no effect on Ca²⁺ current in cells dialyzed with GDP-S. To determine whether NE was inhibiting N- and/or P/Q-type channels, we applied NE in the presence of -conotoxin MVIIC (MVIIC). In the presence of 2.5 µM MVIIC, NE was equally potent at inhibiting the Ca²⁺ current (23 ± 4% vs. 23 ± 4% in control), suggesting that NE was not exclusively inhibiting N- or P/Q-type channels. NE was also equally potent (30 ± 2% vs. 26 ± 4% in control) at inhibiting the Ca²⁺ current in the presence of 2 µM nisoldipine, suggesting that NE was not inhibiting L-type channels. Further, NE inhibited a significantly larger proportion (47 ± 6%) of the resistant Ca²⁺ current remaining in the presence of NISO and MVIIC. These results suggest that NE inhibition of Ca²⁺ current in rabbit CB glomus cells is mediated in most part by effects on the resistant, non L-, N-, or P/Q-type channel and involves a direct G protein interaction with this channel.

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