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Nitric oxide inhibits neuroendocrine Ca_V1 L-channel gating via cGMP-dependent protein kinase in cell-attached patches of bovine chromaffin cells

Valentina Carabelli, Marcello D'Ascenzo *, Emilio Carbone and Claudio Grassi *

Nitric oxide (NO) regulates the release of catecholamines from the adrenal medulla but the molecular targets of its action are not yet well identified. Here we show that the NO donor sodium nitroprusside (SNP, 200 µM) causes a marked depression of the single Ca_V1 L-channel activity in cell-attached patches of bovine chromaffin cells. SNP action was complete within 3-5 min of cell superfusion. In multichannel patches the open probability (NP_o) decreased by ~60 % between 0 and +20 mV. Averaged currents over a number of traces were proportionally reduced and showed no drastic changes to their time course. In single-channel patches the open probability (P_o) at +10 mV decreased by the same amount as that of multichannel patches (~61 %). Such a reduction was mainly associated with an increased probability of null sweeps and a prolongation of mean shut times, while first latency, mean open time and single-channel conductance were not significantly affected. Addition of the NO scavenger carboxy-PTIO or cell treatment with the guanylate cyclase inhibitor ODQ prevented the SNP-induced inhibition. 8-Bromo-cyclicGMP (8-Br-cGMP; 400 µM) mimicked the action of the NO donor and the protein kinase G blocker KT-5823 prevented this effect. The depressive action of SNP was preserved after blocking the cAMP-dependent up-regulatory pathway with the protein kinase A inhibitor H89. Similarly, the inhibitory action of 8-Br-cGMP proceeded regardless of the elevation of cAMP levels, suggesting that cGMP/PKG and cAMP/PKA act independently on L-channel gating. The inhibitory action of 8-Br-cGMP was also independent of the G protein-induced inhibition of L-channels mediated by purinergic and opiodergic autoreceptors. Since Ca²⁺ channels contribute critically to both the local production of NO and catecholamine release, the NO/PKG-mediated inhibition of neuroendocrine L-channels described here may represent an important autocrine signalling mechanism for controlling the rate of neurotransmitter release from adrenal glands.

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