Channelpedia

PubMed 23343624


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Kv1.4 , Kv3.1 , Kv4.2 , Kv4.3



Title: Mechanisms responsible for the trophic effect of beta-adrenoceptors on the I(to) current density in type 1 diabetic rat cardiomyocytes.

Authors: Raúl Setién, Aintzane Alday, Cristina Diaz-Asensio, Janire Urrutia, Mónica Gallego, Oscar Casis

Journal, date & volume: Cell. Physiol. Biochem., 2013 , 31, 25-36

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23343624


Abstract
In diabetic ventricular myocytes, transient outward potassium current (Ito) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on Ito since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (βAR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the βAR agonist isoproterenol recovers Ito amplitude to normal values.Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. Ito current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation.Stimulation of βAR activates first a Gαs protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the Gαi protein. This leads to the activation of the βAR-Kinase-1 and further receptor phosphorylation and arrestin dependent internalization. The internalized receptor-arrestin complex recruits and activates cSrc and the MAPK cascade, where Ras, c-Raf1 and finally ERK1/2 mediate the increase in Kv4.2 and Kv4.3 protein abundance in the plasma membrane.β2AR stimulation activates a Gαs and Gαi protein dependent pathway where the ERK1/2 modulates the Ito current amplitude and the density of the Kv4.2 and Kv4.2 channels in the plasma membrane upon sympathetic stimulation in diabetic heart.