When Is cAMP Not cAMP?

any important cellular processes are controlled via stimulation (or inhibition) of signal transduction systems, among which heptahelical G proteincoupled receptors (GPCRs) figure prominently.A classical example in cardiac myocytes is the ␤-adrenergic receptor (␤-AR) cascade (see Figure , panel A), which leads to positive inotropic and lusitropic effects. 1 Occupation of the ␤-ARs by an agonist activates a GTP binding protein (G s ), such that the ␣ subunit dissociates and activates adenylyl cyclase (AC), thereby producing cAMP.The increase in cAMP leads to the dissociation of the regulatory and catalytic subunits of protein kinase A (PKA).PKA can be tethered near its substrates by an A-kinase anchoring protein (AKAP).The PKA catalytic subunit phosphorylates several key myocyte proteins involved in excitation-contraction (E-C) coupling, including the L-type Ca 2ϩ channel, phospholamban (PLB), ryanodine receptor (RyR), myosin binding protein C, and troponin I (TnI).These effects produce PKA-dependent increases in Ca 2ϩ current (I Ca ), sarcoplasmic reticulum (SR) Ca 2ϩ uptake and release, as well as a desensitization of the myofilaments to Ca 2ϩ .The net result is the characteristic positive inotropic and lusitropic effects of ␤-AR activation in cardiac myocytes.The stimulatory effects of GPCR activation can be inhibited at several levels.The receptor can be desensitized by G protein receptor kinases (eg, ␤-ARK) and arrestins.2 The activation of AC by G s␣ can be antagonized by an inhibitory G protein (G i ), which can be activated by muscarinic receptors (and may also be coactivated during ␤ 2 -AR activa- tion).[3][4][5] The effects of cAMP can also be limited by cAMP hydrolysis by phosphodiesterases (PDEs).The PKA phosphorylation target can also be dephosphorylated by phosphatases.Thus, there are many points where regulation can occur, and all of these proteins can occur in different isoforms creating a rich montage of PKA-dependent regulation of cardiac myocyte function.Indeed, the proximity to PKA targets, local amounts of regulatory proteins, and different isoforms can create highly specialized local signaling between a given hormone and its cellular targets, even when the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.