Adrenergic Fight-or-Flight

In this issue of Circulation Research , Irie et al1 demonstrate novel aspects of crosstalk downstream of β-adrenergic receptors (β-AR) between classical cAMP-dependent protein kinase (PKA) target proteins and nitric oxide synthase (NOS) signaling in cardiac myocytes. This study opens up intriguing new questions for this field.Article, see p 793 The classic and simple story of β-AR–induced cardiac inotropy that we typically teach students (depending on the level) is as follows. β-AR stimulation by norepinephrine or epinephrine stimulates Gs-dependent activation of adenylyl cyclase, which produces cAMP that activates PKA to phosphorylate key target proteins in excitation–contraction coupling. Key functional targets that we discuss are the L-type Ca channel, phospholamban (PLN), and troponin I (TnI).2 Sometimes we also include myosin-binding protein C, the ryanodine receptor, phospholemman (that modulates the Na/K-ATPase akin to PLN regulation of the sarcoplasmic reticulum [SR] Ca-ATPase [SERCA]), delayed rectifier K+ channels (IKr and IKs), and Cl− channels (ICFTR and ICl(Ca)).3 So even from the simple β-AR–cAMP–PKA pathway, there are many targets that produce meaningful functional effects in the integrated β-AR fight-or-flight response. But, based on our recent analysis,3 the main targets likely to contribute quantitatively to β-AR– and PKA-induced inotropy and lusitropy are L-type Ca channel, PLN, phospholemman, IKs, TnI, and myosin-binding protein C. My own simple functional model is that (1) the L-type Ca channel and PLN/SERCA effects elevate cellular and SR Ca2+ content, which causes a major increase in Ca transient amplitude, (2) phospholemman and IKs effects temper the rise in myocyte Ca2+ by enhancing Na+ extrusion via the Na pump and limiting action potential duration, respectively, (3) PLN/SERCA and TnI mediate lusitropy by accelerating [Ca2+]i decline and Ca2+ dissociation from …