Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the I-to Current Density in Type 1 Diabetic Rat Cardiomyocytes

Background/Aims: In diabetic ventricular myocytes, transient outward potassium current (I-to) amplitude is severely reduced because of the impaired catecholamine release that characterizes diabetic autonomic neuropathy. Sympathetic nervous system exhibits a trophic effect on I-to since incubation of myocytes with noradrenaline restores current amplitude via beta-adrenoceptor (beta AR) stimulation. Here, we investigate the intracellular signalling pathway though which incubation of diabetic cardiomyocytes with the beta AR agonist isoproterenol recovers I-to amplitude to normal values. Methods: Experiments were performed in ventricular myocytes isolated from streptozotocin-diabetic rats. I-to current was recorded by using the patch-clamp technique. Kv4 channel expression was determined by immunofluorescence. Protein-protein interaction was determined by coimmunoprecipitation. Results: Stimulation of beta AR activates first a G alpha s protein, adenylyl cyclase and Protein Kinase A. PKA-phosphorylated receptor then switches to the G alpha i protein. This leads to the activation of the beta AR-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. Conclusion: beta(2)AR stimulation activates a G alpha s and G alpha i 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.

Perinatal hipoxic ischemic injury in the auditory pathway and the effect of several neuroprotective agents

192 p.

La gestión del turismo en los programas de innovación rural de Castilla-La Mancha

[ES] Los programas de innovación rural han supuesto un verdadero revulsivo para determinadas regiones europeas, por cuanto han representado una cuantiosa inversión que ha necesitado de una adecuada gestión para dirigir el destino de unos fondos estructurales. En este sentido, el presente trabajo analiza la inversión de estos programas de desarrollo en medidas de apoyo al sector del turismo rural, que han supuesto un importante incremento de la oferta a diversos niveles: aumento de alojamientos rurales, del número de plazas disponibles para turistas, rehabilitación del patrimonio, puesta en valor de elementos históricos y recuperación, en definitiva, del patrimonio histórico, cultural, arquitectónico y natural del mundo rural.