CALL FOR PAPERS Cardiovascular and Cerebrovascular Aging–New Mechanisms and Insights Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca signaling

Liu J, Sirenko S, Juhaszova M, Sollott SJ, Shukla S, Yaniv Y, Lakatta EG. Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca signaling. Am J Physiol Heart Circ Physiol 306: H1385–H1397, 2014. First published March 14, 2014; doi:10.1152/ajpheart.00088.2014.—A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca clock, and the electrogenic-sarcolemmal membrane clock. Ca activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na /Ca exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca -cycling proteins, including SR Ca -ATPase pump, ryanodine receptors, and Na /Ca exchanger. Thus a deterioration in intrinsic Ca clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.