A TREK-1–Like Potassium Channel in Atrial Cells Inhibited by β-Adrenergic Stimulation and Activated by Volatile Anesthetics

Abstract

Abstract-Many members of the two-pore-domain potassium (K ϩ ) channel family have been detected in the mammalian heart but the endogenous correlates of these channels still have to be identified. We investigated whether I KAA , a background K ϩ current activated by negative pressure (stretch) and by arachidonic acid (AA) and sensitive to intracellular acidification, could be the native correlate of TREK-1 in adult rat atrial cells. Using the inside-out configuration of the patch-clamp technique, we found that I KAA , like TREK-1, was outwardly rectifying in physiological K ϩ conditions, with a conductance of 41 pS at ϩ50 mV. Like TREK-1, I KAA was reversibly activated by clinical concentrations of volatile anesthetics (in mmol/L, chloroform 0.18, halothane 0.11, and isoflurane 0.69). In cell-attached experiments, I KAA was inhibited by chlorophenylthio-cAMP (500 mol/L) and also by stimulation of ␤-adrenergic receptors with isoproterenol (1 mol/L). In addition, TREK-1 mRNAs were detected in all cardiac tissues, and the TREK-1 protein was immunolocalized in isolated atrial myocytes. Such a background potassium channel might contribute to the positive inotropic effects produced by ␤-adrenergic stimulation of the heart. It might also be involved in the regulation of the atrial natriuretic peptide secretion. Key Words: potassium channels Ⅲ volatile anesthetics Ⅲ ␤-adrenergic receptor Ⅲ heart cells C ardiac potassium (K ϩ ) channels have extensively been studied for years. In the working atrial and ventricular myocytes, they belong to the following two major families: (1) the voltage-dependent channels (I to , I Kr , I Ks , etc), which are involved in the different repolarization phases of the cardiac action potential (AP), and (2) the background K ϩ channels, which stabilize the resting membrane potential at a hyperpolarized level and regulate AP duration in physiological conditions (I K1 ), during sympathetic stimulation of the heart (I KACh ), or during pathological events such as ischemia (I KATP , etc) (for a review, see Carmeliet 1 ).During the last decade, a large number of K ϩ channel ␣ subunits were cloned and further characterized in expression systems such as Xenopus oocytes and mammalian cell lines (COS, HEK, etc). Some of these cloned channels were proposed as molecular substrates for the endogenous cardiac K ϩ currents on the basis of their biophysical and pharmacological properties. For instance, Kv4.2 is suggested to be a molecular correlate of I to , whereas HERG and KvLQT1/Isk correspond to I Kr and I Ks , respectively. 2-6 IRK1 (Kir2.1) generates a current similar to that of I K1 , whereas GIRK1 (Kir3.1) forms a complex with GIRK4 (Kir3.4) to reproduce I KACh . 7,8 Kir6.2 coassembles with the sulfonylurea receptor SUR2A to reconstitute the cardiac K ATP channel. 9,10 However, not all cloned K ϩ channel ␣ subunits shown to be expressed in the heart have been associated with an endogenous channel. This is particularly the case for the expanding family of mammalian two-pore-domain potassium (K 2P ) cha...

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…TREK‐1 expression has been reported throughout all regions of the heart3, 8, 10, 36; however, few data are available on relative levels of expressed protein in SAN, atrium, and ventricle. TREK‐1 protein expression was assessed in different mouse heart regions to determine whether differential expression could contribute to the predominant SAN phenotypes observed in αMHC‐ Kcnk2 f/f mice.…”

“…TREK‐1 is highly expressed in the nervous system, where it regulates depression phenotypes and nociception. Expression of TREK‐1 has also been identified in heart with proposed roles in regulation of myocyte membrane excitability,7, 8, 9, 10, 11, 12, 13, 14 although its role in specific cardiac phenotypes remains unclear.…”

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium

“…However, Western blotting of murine and rat brain revealed a single band of , 92 kDa. This antibody recognised only a single band of , 45 kDa when subsequently used to blot rat heart microsomes (Terrenoire et al 2001). A core size for TREK1 has been estimated to be 44 kDa (Hervieu et al 2001).…”

Mechanosensitive ion channels: molecules of mechanotransduction

“…stretch, cell swelling, intracellular acidosis, heat and voltage) (Maingret et al, 1999b;Maingret et al, 2000a;Maingret et al, 2002) and chemical stimuli (e.g. polyunsaturated fatty acids, lysophospholipids, membrane crenators and volatile general anesthetics) (Patel et al, 1998;Maingret et al, 2000b;Patel et al, 1999;Terrenoire et al, 2001). Their activity is downmodulated by phosphorylation of a C-terminal serine residue by cAMP-dependent protein kinase (PKA) (Bockenhauer et al, 2001).…”