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ORIGINAL ARTICLE

Potentiation of P2Y Receptors by Physiological Elevations of Extracellular K⁺ via a Mechanism Independent of Ca²⁺ Influx

Departments of Physiology (S.J.P., J.M.-P., M.P.M.-S.) and Pharmacology (E.A.B.), University of Cambridge, Cambridge, United Kingdom

Abstract

Many physiological and pathophysiological situations generate a significant increase in extracellular K⁺ concentration. This is known to influence a number of membrane conductances and exchangers, whereas direct effects of K⁺ on the activation of G protein-coupled receptors have not been reported. We now show that Ca²⁺ release evoked by P2Y₁ receptors expressed in 1321-N1 astrocytoma cells is markedly potentiated by small increases in external K⁺ concentration. This effect was blocked by the phospholipase-C inhibitor U-73122 (1-[6-[[17]-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), but not by its analog U-73343 (1-[6-[[17]-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5-pyrrolidinedione), and not by nifedipine, Ni²⁺, Cd²⁺, or Gd³⁺. Thus, K⁺ enhances D-myo-inositol 1,4,5-trisphosphate-dependent Ca²⁺ release without a requirement for Ca²⁺ influx. The cation dependence of this effect displayed the order K⁺ > Rb⁺ > N-methyl-D-glucamine⁺, and Cs⁺ and choline⁺ were ineffective. The potentiation by K⁺ is half-maximal at an increase of 2.6 mM (total K⁺ of 7.6 mM). K⁺ caused a reduction in EC₅₀ (2.7-fold for a 29 mM increase) without a change of slope; thus, the greatest effect was observed at near-threshold agonist levels. The response to K⁺ can be explained in part by depolarization-dependent potentiation of P2Y₁ receptors [J Physiol (Lond) 555:61–70, 2004]. However, electrophysiological recordings of 1321-N1 cells and megakaryocytes demonstrated that K⁺ also amplifies ADP-evoked Ca²⁺ responses independently of changes in membrane potential. Elevated K⁺ also amplified endogenous UTP-dependent Ca²⁺ responses in human embryonic kidney 293 cells, suggesting that other P2Y receptors are K⁺-dependent. P2Y receptors display a widespread tissue distribution; therefore, their modulation by small changes in extracellular K⁺ may represent a novel means of autocrine and paracrine regulation of cellular activity.

Address correspondence to: Dr. Martyn Mahaut-Smith, Department of Physiology, University of Cambridge, Downing St., CB2 3EG, UK. E-mail: mpm11{at}cam.ac.uk.

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