Fig. 1. Interrelation between β³-adrenergic receptor (AR) and the major sympathetic and parasympathetic signaling pathways in cardiomyocytes. In the inotropic β¹- and β²-AR signaling path (  red arrows  ) protein kinase A (PKA) coordinates (1) positive inotropy by increasing intracellular Ca²⁺(stimulation by phosphorylation of the L-type Ca²⁺channel, of the sarcoplasmatic reticulum [SR] Ca²⁺pump [SERCA] directly and indirectly by relieving its repression by phospholamban [PLN], and of the sarcoplasmatic reticulum Ca²⁺release channel [RYR]); (2) positive lusitropy by removing cytoplasmic Ca²⁺  via the Na–Ca²⁺exchanger and decreasing the affinity of Ca²⁺binding to Ca²⁺binding troponin subunit (TNC) by phosphorylation of inhibitory troponin subunit (TNI); (3) negative adrenergic feedback by desensitization of β¹-ARs (phosphorylation by PKA and G protein–coupled receptor kinase [GRK]); and (4) stimulation of adenosine triphosphate production in the mitochondria by Ca²⁺. β³-AR signaling (  blue arrows ) counterbalances the canonical β¹- and β²-AR path  via Gi and nitric oxide (NO) production as well as by enhancing the vagal tone by facilitation of acetylcholine (AcC) release from the parasympathetic nerve terminals acting through the muscarinic acetylcholine receptor 2 (M2). Norepinephrine (NE) release from the sympathetic nerve terminals exerts a second negative feedback loop.  Arrows denote stimulation, and  blunted ends  denote inhibition. AC = adenylyl cyclase; DAG = diacylglycerol; GC = soluble guanylyl cyclase; Gi and Gs = inhibitory and stimulatory G-protein α subunits; L = L-type slow Ca²⁺-channel; NOS = nitric oxide synthase; PDK = 3-phosphoinositide–dependent kinase; PI3K = phosphoinositide-3 kinase; PKA, PKB, PKC, and PKG = target-specific Ser/Thr protein kinases; PLC = phospholipase C; PNT = parasympathetic nerve terminal; SNT = sympathetic nerve terminal; Z = sarcomeric Z disc.