β-adrenergic-mediated dynamic augmentation of sarcolemmal Ca V 1.2 clustering and co-operativity in ventricular myocytes

摘要: Author(s): Ito, Danica W; Hannigan, Karen I; Ghosh, Debapriya; Xu, Bing; Del Villar, Silvia G; Xiang, Yang K; Dickson, Eamonn J; Navedo, Manuel F; Dixon, Rose E | Abstract: Key pointsPrevailing dogma holds that activation of the β-adrenergic receptor/cAMP/protein kinase A signalling pathway leads to enhanced L-type CaV 1.2 channel activity, resulting in increased Ca2+ influx into ventricular myocytes and a positive inotropic response. However, full mechanistic molecular details underlying this phenomenon are incompletely understood. clusters decorate T-tubule sarcolemmas myocytes. Within clusters, nanometer proximity between channels permits -dependent co-operative gating behaviour mediated by physical interactions adjacent C-terminal tails. We report stimulation cardiomyocytes with isoproterenol, evokes dynamic, protein A-dependent augmentation abundance along cardiomyocyte T-tubules, appearance 'super-clusters', co-operativity amplifies influx. On basis these data, we suggest new model which sub-sarcolemmal pool pre-synthesized resides can be mobilized membrane times high haemodynamic or metabolic demand, tune excitation-contraction coupling.AbstractVoltage-dependent play an indispensable role cardiac coupling. Activation receptor (βAR)/cAMP/protein (PKA) exhibit clustered distribution sarcolemma where physical, allosteric This augments myocyte transient contraction amplitudes. investigated whether βAR could alter clustering facilitate elevate Bimolecular fluorescence complementation experiments reveal agonist, isoproterenol (ISO), promotes 1.2-CaV interactions. Super-resolution nanoscopy dynamic tracking indicate expedited spatial channels, 'super-clusters' z-lines ISO-stimulated cardiomyocytes. The mechanism super-cluster formation involves rapid, sarcolemmal after ISO application. Optical electrophysiological single recordings confirm newly inserted functional contribute overt stimulated results present study facet βAR-mediated regulation heart support novel concept channel-containing vesicles/endosomes coupling meet and/or demands.