Potential of β2AR for added benefit in treating heart failure through a better understanding of signaling

Abstract

In the human heart, adrenaline activates the β₂-adrenoceptor (β₂AR) to cause powerful increases in contractile force and acceleration of contraction. This is explained by tight coupling of the β₂AR to the Gsα-protein–cyclic AMP–PKA signaling pathway with phosphorylation of proteins, including the L-type Ca²⁺ channel, ryanodine receptor, phospholamban, and sarcomeric proteins troponin I and C-protein. Experimentally, it has been shown that activation of β₂ARs is arrhythmogenic in the human failing heart. From cell- and animal model-based experiments, there is increased awareness of the broader signaling repertoire of the β₂AR. The β₂AR has the ability to couple simultaneously to Gsα- and Giα-proteins and activate β-arrestin signaling pathways. In addition to the orthosteric binding site, modes of conformation stabilization exist through the allosteric binding site and with pepducins. Beneficial effects, including cardioprotection, have been observed, waiting for translation to the human diseased heart and fuelling optimism for advancement of therapeutics for heart disease.