Selective inhibition of M‐type potassium channels in rat sympathetic neurons by uridine nucleotide preferring receptors

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Abstract
UTP and UDP depolarize rat superior cervical ganglion neurons and trigger noradrenaline release from these cells. The present study investigated the mechanisms underlying this excitatory action of uridine nucleotides by measuring whole‐cell voltage‐dependent K+ and Ca2+ currents. Steady‐state outward (holding) currents measured in the amphotericin B perforated‐patch configuration at a potential of −30 mV were reduced by 10 μm UTP in a reversible manner, but steady‐state inward (holding) currents at −70 mV were not affected. This action of UTP was shared by the muscarinic agonist oxotremorine‐M. In current‐voltage curves between −20 and −100 mV, UTP diminished primarily the outwardly rectifying current components arising at potentials positive to −60 mV. Slow relaxations of muscarinic K+ currents (IM) evoked by hyperpolarizations from −30 to −55 mV were also reduced by 10 μm UTP (37% inhibition) and oxotremorine‐M (81% inhibition). In contrast, transient K+‐currents, delayed rectifier currents, fast and slow Ca2+‐dependent K+ currents, as well as voltage‐dependent Ca2+ currents were not altered by UTP. In conventional (open‐tip) whole‐cell recordings, replacement of GTP in the pipette by GDPβS abolished the UTP‐induced inhibition of IM, whereas replacement by GTPγS rendered it irreversible. The UTP‐induced reduction of IM was half maximal at 1.5 μm with a maximum of 37% inhibition; UDP was equipotent and equieffective, while ADP was less potent (half maximal inhibition at 29 μm). ATP had no effect at 30 μm. The inhibition of IM induced by 10 μm UTP was antagonized by pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) at 30 μm and by reactive blue 2 at 10 μm, but not by suramin at concentrations up to 30 μm. These results show that rat superior cervical ganglion neurons possess uridine nucleotide preferring P2Y receptors which inhibit KM channels. This effect presumably forms the basis of the excitatory action of uridine nucleotides in rat sympathetic neurons. British Journal of Pharmacology (1998) 124, 1261–1269; doi:10.1038/sj.bjp.0701956