Protein kinase C mediates neurotensin inhibition of inwardly rectifying potassium currents in rat substantia nigra dopaminergic neurons.

Whole-cell voltage-clamp recordings were used to investigate the molecular transduction mechanism by which neurotensin decreases the inwardly rectifying potassium conductance of dopaminergic (DA) neurons acutely isolated from the rat substantia nigra (SN). With sodium-free external solution, neurotensin evoked inward currents by reducing the inwardly rectifying K+ conductance. Neurotensin inhibition of the K+ current was blocked by the internal perfusion of 1 mM GDP-beta-S. When DA neurons were internally perfused with 0.5 mM GTP-gamma-S, the reduction of K+ conductance produced by neurotensin became irreversible. Neurotensin still inhibited K+ currents in DA neurons pretreated with 500 ng/ml pertussis toxin (PTX). Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), prevented neurotensin from decreasing the potassium conductance. Our results propose that neurotensin activates PKC of SN DA neurons via PTX-insensitive G-proteins and that PKC mediates the neurotensin inhibition of inwardly rectifying potassium currents.