CAPON modulates neuronal calcium handling and cardiac sympathetic neurotransmission during dysautonomia in hypertension.
Lu C-J., Hao G., Nikiforova N., Larsen HE., Liu K., Crabtree MJ., Li D., Herring N., Paterson DJ.
Genome-wide association studies implicate a variant in the neuronal nitric oxide synthase adaptor protein (CAPON) in electrocardiographic QT variation and sudden cardiac death. Interestingly, nitric oxide generated by neuronal NO synthase-1 reduces norepinephrine release; however, this pathway is downregulated in animal models of cardiovascular disease. Because sympathetic hyperactivity can trigger arrhythmia, is this neural phenotype linked to CAPON dysregulation? We hypothesized that CAPON resides in cardiac sympathetic neurons and is a part of the prediseased neuronal phenotype that modulates calcium handling and neurotransmission in dysautonomia. CAPON expression was significantly reduced in the stellate ganglia of spontaneously hypertensive rats before the development of hypertension compared with age-matched Wistar-Kyoto rats. The neuronal calcium current (ICa; n=8) and intracellular calcium transient ([Ca(2+)]i; n=16) were significantly larger in the spontaneously hypertensive rat than in Wistar-Kyoto rat (P<0.05). A novel noradrenergic specific vector (Ad.PRSx8-mCherry/CAPON) significantly upregulated CAPON expression, NO synthase-1 activity, and cGMP in spontaneously hypertensive rat neurons without altering NO synthase-1 levels. Neuronal ICa and [Ca(2+)]i were significantly reduced after CAPON transduction compared with the empty vector. In addition, Ad.PRSx8-mCherry/CAPON also reduced (3)H-norepinephrine release from spontaneously hypertensive rat atria (n=7). NO synthase-1 inhibition (AAAN, 10 μmol/L; n=6) reversed these effects compared with the empty virus alone. In conclusion, targeted upregulation of CAPON decreases cardiac sympathetic hyperactivity. Moreover, dysregulation of this adaptor protein in sympathetic neurons might further amplify the negative cardiac electrophysiological properties seen with CAPON mutations.