Acute desensitization of GIRK current in rat atrial myocytes is related to K+ current flow.
We have investigated the acute desensitization of acetylcholine-activated GIRK current (I(K(ACh))) in cultured adult rat atrial myocytes. Acute desensitization of I(K(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 micromol l(-1)) of ACh. Under this condition experimental manoeuvres that cause a decrease in the amplitude of I(K(ACh)), such as partial block of M2 receptors by atropine, intracellular loading with GDP-beta-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 micromol 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 (I(K(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 I(K(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 I(K(ACh)). Since the ACh-induced hyperpolarization shows comparable desensitization properties as I(K(ACh)), this novel current-dependent desensitization is a physiologically relevant process, shaping the time course of parasympathetic bradycardia.
Bender
Kirsten
K
Department of Physiology, Ruhr-University Bochum, D-44780 Bochum, Germany.
Wellner-Kienitz
Marie-Cécile
MC
Bösche
Leif I
LI
Rinne
Andreas
A
Beckmann
Christian
C
Pott
Lutz
L
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D000109:Acetylcholine; D011188:Potassium