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1 Department of Physiology, Ruhr-University Bochum, D-4480 Bochum, Germany
We have investigated the acute desensitization of acetylcholine-activated GIRK current (IK(ACh)) in cultured adult rat atrial myocytes. Acute desensitization of IK(ACh) is observed as a partial relaxation of current with a half-time of < 5 s when muscarinic M2 receptors are stimulated by a high concentration (> 2 µmol l–1) of ACh. Under this condition experimental manoeuvres that cause a decrease in the amplitude of IK(ACh), such as partial block of M2 receptors by atropine, intracellular loading with GDP-ß-S, or exposure to Ba2+, caused a reduction in desensitization. Acute desensitization was also identified as a decrease in current amplitude and a blunting of the response to saturating [ACh] (20 µmol l–1) when the current had been partially activated by a low concentration of ACh or by stimulation of adenosine A1 receptors. A reduction in current analogous to acute desensitization was observed when ATP-dependent K+ current (IK(ATP)) was activated either by mitochondrial uncoupling using 2,4-dinitrophenole (DNP) or by the channel opener rilmakalim. Adenovirus-driven overexpression of Kir2.1, a subunit of constitutively active inwardly rectifying K+ channels, resulted in a large Ba2+-sensitive background K+ current and a dramatic reduction of ACh-activated current. Adenovirus-driven overexpression of GIRK4 (Kir3.4) subunits resulted in an increased agonist-independent GIRK current paralleled by a reduction in IK(ACh) and removal of the desensitizing component. These data indicate that acute desensitization depends on K+ current flow, independent of the K+ channel species, suggesting that it reflects a reduction in electrochemical driving force rather than a bona fide signalling mechanism. This is supported by the observation that desensitization is paralleled by a significant negative shift in reversal potential of IK(ACh). Since the ACh-induced hyperpolarization shows comparable desensitization properties as IK(ACh), this novel current-dependent desensitization is a physiologically relevant process, shaping the time course of parasympathetic bradycardia.
(Received 2 August 2004;
accepted after revision 27 September 2004;
first published online 30 September 2004)
Corresponding author L. Pott: Department of Physiology, Ruhr-University Bochum, D-44780 Bochum, Germany. Email: lutz.pott{at}rub.de
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