A-Kinase Anchoring Proteins
Getting to the Heart of the Matter
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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 Ca2+ influx through L-type Ca2+ channels, which activates intracellular Ca2+ release via ryanodine receptors located in the sarcoplasmic reticulum (SR) and thus induces a global increase in [Ca2+]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 α-, β-, …