Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Activation of inwardly rectifying Kir2.x potassium channels by beta 3-adrenoceptors is mediated via different signaling pathways with a predominant role of PKC for Kir2.1 and of PKA for Kir2.2.
Scherer D, Kiesecker C, Kulzer M, Günth M, Scholz EP, Kathöfer S, Thomas D, Maurer M, Kreuzer J, Bauer A, Katus HA, Karle CA, Zitron E.
???displayArticle.abstract???
beta(3)-adrenoceptors have recently been shown to induce a complex modulation of intracellular signaling pathways including cyclic guanine monophosphate, cyclic adenosine monophosphate, nitric oxide, and protein kinases A and C. They are expressed in a broad variety of tissues including the myocardium, vascular smooth muscle, and endothelium. In those tissues, resting membrane potential is controlled mainly by inwardly rectifying potassium channels of the Kir2 family namely, Kir2.1 in the vascular smooth muscle, Kir2.1-2.3 in the myocardium, and Kir2.1-2.2 in the endothelium. In the present study, we investigated the possible modulation of Kir2 channel function by beta(3)-adrenoceptors in an expression system. Human-cloned beta(3)-adrenoceptors and Kir2.1 (KCNJ2), Kir2.2 (KCNJ12), and Kir2.3 (KCNJ4) channels were coexpressed in Xenopus oocytes, and currents were measured with double-microelectrode voltage clamp. Activation of beta(3)-adrenoceptors with isoproterenol resulted in markedly increased currents in Kir2.1 and in Kir2.2 potassium channels with EC50 values of 27 and 18 nM, respectively. In contrast, Kir2.3 currents were not modulated. Coapplication of specific inhibitors of protein kinase A (KT-5720) and calmodulin kinase II (KN-93) had no effects on the observed regulation in Kir2.1. However, coapplication of protein kinase C (PKC) inhibitors staurosporine and chelerythrine suppressed the observed effect. In Kir2.2, coapplication of KT-5720 reduced the effect of beta(3)-adrenoceptor activation. No differences in current increase after application of isoproterenol were observed between mutant Kir2.2 potassium channels lacking all functional PKC phosphorylation sites and Kir2.2 wild-type channels. In heteromeric Kir2.x channels, all types of heteromers were activated. The effect was most pronounced in Kir2.1/Kir2.2 and in Kir2.2/Kir2.3 channels. In summary, homomeric and heteromeric Kir2.x channels are activated by beta(3)-adrenoceptors via different protein kinase-dependent pathways: Kir2.1 subunits are modulated by PKC, whereas Kir2.2 is modulated by protein kinase A. In heteromeric composition, a marked activation of currents can be observed particularly with involvement of Kir2.2 subunits. This regulation may contribute to the hyperpolarizing effects of beta(3)-adrenoceptors in tissues that exhibit modulation by Kir2 channel function.
Anthony,
Localization of the beta(beta)3-adrenoceptor in the human gastrointestinal tract: an immunohistochemical study.
1998, Pubmed
Anthony,
Localization of the beta(beta)3-adrenoceptor in the human gastrointestinal tract: an immunohistochemical study.
1998,
Pubmed Berkowitz,
Distribution of beta 3-adrenoceptor mRNA in human tissues.
1995,
Pubmed Bosch,
beta3-Adrenergic regulation of an ion channel in the heart-inhibition of the slow delayed rectifier potassium current I(Ks) in guinea pig ventricular myocytes.
2002,
Pubmed
,
Xenbase Brodde,
Adrenergic and muscarinic receptors in the human heart.
1999,
Pubmed Brodde,
Cardiac adrenoceptors: physiological and pathophysiological relevance.
2006,
Pubmed Chamberlain,
The tissue distribution of the human beta3-adrenoceptor studied using a monoclonal antibody: direct evidence of the beta3-adrenoceptor in human adipose tissue, atrium and skeletal muscle.
1999,
Pubmed Couldwell,
Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines.
1994,
Pubmed Dessy,
Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization.
2004,
Pubmed Dessy,
Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol.
2005,
Pubmed Dhamoon,
Unique Kir2.x properties determine regional and species differences in the cardiac inward rectifier K+ current.
2004,
Pubmed Fakler,
Kir2.1 inward rectifier K+ channels are regulated independently by protein kinases and ATP hydrolysis.
1994,
Pubmed
,
Xenbase Fang,
Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2.
2005,
Pubmed Ferro,
beta-adrenoceptors and potassium channels.
2006,
Pubmed Gauthier,
Beta3-adrenoceptors in the cardiovascular system.
2000,
Pubmed Gauthier,
Functional beta3-adrenoceptor in the human heart.
1996,
Pubmed Gauthier,
Interspecies differences in the cardiac negative inotropic effects of beta(3)-adrenoceptor agonists.
1999,
Pubmed Henry,
Protein kinase C inhibition of cloned inward rectifier (HRK1/KIR2.3) K+ channels expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase Jantzi,
Inward rectifying potassium channels facilitate cell-to-cell communication in hamster retractor muscle feed arteries.
2006,
Pubmed Karle,
Human cardiac inwardly-rectifying K+ channel Kir(2.1b) is inhibited by direct protein kinase C-dependent regulation in human isolated cardiomyocytes and in an expression system.
2002,
Pubmed
,
Xenbase Kathöfer,
Functional coupling of human beta 3-adrenoreceptors to the KvLQT1/MinK potassium channel.
2000,
Pubmed
,
Xenbase Kathöfer,
Human beta(3)-adrenoreceptors couple to KvLQT1/MinK potassium channels in Xenopus oocytes via protein kinase C phosphorylation of the KvLQT1 protein.
2003,
Pubmed
,
Xenbase Kiesecker,
Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1.
2006,
Pubmed
,
Xenbase Kim,
Contribution of Na+-K+ pump and KIR currents to extracellular pH-dependent changes of contractility in rat superior mesenteric artery.
2005,
Pubmed Koumi,
Beta-adrenergic and cholinergic modulation of inward rectifier K+ channel function and phosphorylation in guinea-pig ventricle.
1995,
Pubmed Koumi,
beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts.
1995,
Pubmed Koumi,
beta-adrenergic and cholinergic modulation of the inwardly rectifying K+ current in guinea-pig ventricular myocytes.
1995,
Pubmed Leblais,
beta3-adrenoceptor control the cystic fibrosis transmembrane conductance regulator through a cAMP/protein kinase A-independent pathway.
1999,
Pubmed Liu,
Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes.
2001,
Pubmed
,
Xenbase Lopatin,
Inward rectifiers in the heart: an update on I(K1).
2001,
Pubmed Matsushita,
Characterization of beta 3-adrenoceptor-mediated relaxation in rat abdominal aorta smooth muscle.
2003,
Pubmed Miake,
Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression.
2003,
Pubmed Nichols,
Inward rectifier potassium channels.
1997,
Pubmed Nilius,
Ion channels and their functional role in vascular endothelium.
2001,
Pubmed Park,
Activation of inward rectifier K+ channels by hypoxia in rabbit coronary arterial smooth muscle cells.
2005,
Pubmed Plaster,
Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.
2001,
Pubmed
,
Xenbase Preisig-Müller,
Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome.
2002,
Pubmed
,
Xenbase Priori,
A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene.
2005,
Pubmed Rockman,
Seven-transmembrane-spanning receptors and heart function.
2002,
Pubmed Schram,
Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents.
2003,
Pubmed
,
Xenbase Soeder,
The beta3-adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism.
1999,
Pubmed Sterin-Borda,
Role of nitric oxide/cyclic GMP and cyclic AMP in beta3 adrenoceptor-chronotropic response.
2006,
Pubmed Tamaoki,
Atypical adrenoceptor-mediated relaxation of canine pulmonary artery through a cAMP-dependent pathway.
1998,
Pubmed Thomas,
Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X).
2004,
Pubmed
,
Xenbase Töpert,
Kir2.4: a novel K+ inward rectifier channel associated with motoneurons of cranial nerve nuclei.
1998,
Pubmed
,
Xenbase Trochu,
Beta 3-adrenoceptor stimulation induces vasorelaxation mediated essentially by endothelium-derived nitric oxide in rat thoracic aorta.
1999,
Pubmed Witchel,
Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes.
2002,
Pubmed
,
Xenbase Zaritsky,
Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.
2000,
Pubmed Zaritsky,
The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes.
2001,
Pubmed Zheng,
Emerging concepts and therapeutic implications of beta-adrenergic receptor subtype signaling.
2005,
Pubmed Zhu,
Suppression of Kir2.3 activity by protein kinase C phosphorylation of the channel protein at threonine 53.
1999,
Pubmed
,
Xenbase Zitron,
QTc prolongation by grapefruit juice and its potential pharmacological basis: HERG channel blockade by flavonoids.
2005,
Pubmed
,
Xenbase Zitron,
Human cardiac inwardly rectifying current IKir2.2 is upregulated by activation of protein kinase A.
2004,
Pubmed
,
Xenbase Zobel,
Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2.
2003,
Pubmed
