Deval Emmanuel, Salinas Miguel, Baron Anne, Lingueglia Eric, Lazdunski Michel
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UNSA UMR 6097, Institut Paul Hamel, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
J Biol Chem. 2004 May 7;279(19):19531-9. doi: 10.1074/jbc.M313078200. Epub 2004 Feb 19.
ASIC3, an acid-sensing ion channel subunit expressed essentially in sensory neurons, has been proposed to be involved in pain. We show here for the first time that native ASIC3-like currents were increased in cultured dorsal root ganglion (DRG) neurons following protein kinase C (PKC) stimulation. This increase was induced by the phorbol ester PDBu and by pain mediators, such as serotonin, which are known to activate the PKC pathway through their binding to G protein-coupled receptors. We demonstrate that this regulation involves the silent ASIC2b subunit, an ASIC subunit also expressed in sensory neurons. Indeed, heteromultimeric ASIC3/ASIC2b channels, but not homomeric ASIC3 channels, are positively regulated by PKC. The increase of ASIC3/ASIC2b current is accompanied by a shift in its pH dependence toward more physiological pH values and may lead to an increase of sensory neuron excitability. This regulation by PKC requires PICK-1 (protein interacting with C kinase), a PDZ domain-containing protein, which interacts with the ASIC2b C terminus.
ASIC3是一种主要在感觉神经元中表达的酸敏感离子通道亚基，有人提出它与疼痛有关。我们在此首次表明，蛋白激酶C（PKC）刺激后，培养的背根神经节（DRG）神经元中的天然ASIC3样电流增加。这种增加是由佛波酯PDBu和疼痛介质（如血清素）诱导的，已知这些介质通过与G蛋白偶联受体结合来激活PKC途径。我们证明这种调节涉及沉默的ASIC2b亚基，这也是一种在感觉神经元中表达的ASIC亚基。实际上，异源多聚体ASIC3/ASIC2b通道而非同源ASIC3通道受到PKC的正向调节。ASIC3/ASIC2b电流的增加伴随着其pH依赖性向更生理的pH值转变，可能导致感觉神经元兴奋性增加。PKC的这种调节需要PICK-1（与C激酶相互作用的蛋白质），一种含PDZ结构域的蛋白质，它与ASIC2b的C末端相互作用。
