Getting to the Heart of the Matter

The heart is a sophisticated organ that continuously pumps blood to ensure that oxygen and nutrients reach the brain, other organs, and peripheral tissue. The right side of the heart pumps blood to the lungs, where oxygen is taken up and carbon dioxide is removed. The left side of the heart then pumps blood to the rest of the body, where oxygen and nutrients are delivered to tissues. This cycle is sustained by the repeated contraction of cardiomyocytes, specialized muscle cells that are designed to contract and respond rapidly to physiological stimuli. Normally, contraction of atrial and ventricular myocytes is activated by action potentials that originate in the sinoatrial node in the wall of the right atrium, often referred to as the pacemaker of the heart. Coupling of this electric signal to contraction (EC coupling) in cardiac myocytes is initiated with Ca influx through L-type Ca channels, which activates intracellular Ca release via ryanodine receptors located in the sarcoplasmic reticulum (SR) and thus induces a global increase in [Ca ]i that triggers contraction.1,2 The rate at which the sinoatrial node myocytes fire action potentials is modulated by 2 opposing nervous systems. The sympathetic nervous system uses the catecholamine hormones noradrenaline and adrenaline to increase the force and rate of atrial and ventricular contraction. In contrast, the parasympathetic nervous system releases the neurotransmitter acetylcholine to reduce action potentials from the sinoatrial node. Together, these neural systems ensure that cardiac output is matched to the physiological needs of the organism, a process that is often termed “stimulus-response coupling. ” Although numerous signal-transduction cascades are operational in cardiomyocytes, G-protein–coupled receptor–signaling pathways play a prominent role. Agonists such as noradrenaline, adrenaline, angiotensin II, and endothelin-1 promote the interaction of their respective receptors with a G-protein heterotrimer comprising -, -, and -subunits.3 This transient interaction promotes exchange of GTP for GDP on the G subunit and thereby activates or inhibits effector molecules and ion channels. Effector molecules, which include enzymes such as adenylate adenylyl cyclases and phospholipases, regulate the production of second messengers.3 Second messengers are small molecules that are mobilized or generated in response to extracellular stimuli. In the heart, Ca and cAMP are the second messengers most frequently used by cardiac signaling pathways. They act at defined intracellular sites to initiate signaling events4 that control excitability, contraction, and gene expression. Occupancy of -adrenergic receptors engages the cAMP-signaling pathway to activate protein kinases, guanine nucleotide exchange factors, and ion channels.5,6 Combinations of these cAMPresponsive enzymes modulate cardiac contraction force (inotropy), heart rate (chronotropy), and muscle relaxation (lusitropy). 7 Not surprisingly, there is a significant degree of cross talk between the Ca -and cAMP-signaling pathways. This is achieved in part because Ca -and cAMP-responsive proteins are often brought together in multiprotein complexes.8 The goal of the present review is to highlight recent progress on our understanding of how anchored signaling complexes influence cardiomyocyte physiology. We will focus on cardiomyocyte A-kinase anchoring proteins (AKAPs), a family of scaffolding proteins that compartmentalize cAMPand Ca responsive enzymes in proximity to preferred substrates such as ion channels, contractile proteins, Ca pumps, and the transcriptional machinery.