Lysosomal calcium signalling contributes to the acute α-adrenergic response via calcium-stimulated adenylyl cyclase 1 and 8

Akerman, E.; Capel, R. A.; Read, M.; Song, Q.; Bose, S. J.; Calamaio, S.; Aston, D.; Koschinski, A.; Lloyd, S.; Bell, L.; Rashbrook, V. S.; Keller, M.; Bracher, F.; Potter, B. V.; Rivolta, I.; Galione, A.; Sparrow, D. B.; Conti, A.; Terrar, D. A.; Zaccolo, M.; Burton, R. A. B.

doi:10.1101/2024.11.25.625232

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bioRxiv · 10.1101/2024.11.25.625232

Lysosomal calcium signalling contributes to the acute α-adrenergic response via calcium-stimulated adenylyl cyclase 1 and 8

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Abstract

Inositol trisphosphate (IP3), a calcium (Ca2+)-mobilizing second messenger, releases Ca2+ from the sarcoplasmic reticulum (SR) via IP3 receptors and modulates adenylyl cyclase (AC) activity in atrial myocytes. Lysosomes participate in Ca2+ homeostasis by mobilising Ca2+ in response to Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP). We postulate that both downstream activation of Ca2+ sensitive AC (AC1 and AC8) and lysosomal Ca2+ signalling in response to IP3R activation contribute to atrial myocyte function and pacemaking. Ectopic application of phenylephrine (PE) increased chronotropy and inotropy and this response was reduced in the presence of NAADP pathway inhibitors (BZ-194 and SAN4825) and Bafilomycin A1. PE increased cyclic adenosine 3-5 monophosphate (cAMP) activity in neonatal rat atrial myocytes (NRAMs) and this was inhibited by NAADP pathway inhibitors. This inhibition was not observed in neonatal rat ventricular myocytes (NRVMs), revealing specificity of this response to NRAMs. We investigated expression of AC1 and AC8 as a possible explanation to these observations. Genetic perturbation of AC1 and AC8 by double-knockout of Adcy1 and Adcy8 in a mouse model showed a decrease in positive chronotropic and inotropic response upon cumulative dose of PE in atrial tissue, reduced PE stimulated amplitude of Ca2+ transient in isolated atrial myocytes and presented decreased cytosolic cAMP levels in response to PE in neonatal atrial myocytes that was not inhibited by NAADP pathway inhibitors. Our data identifies a link between NAADP and -adrenergic signalling pathways in atrial myocytes, highlighting that lysosomal Ca2+ is an important component of -adrenergic stimulation in the cardiac atria and warrants further investigation.

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Akerman, E., Capel, R. A., Read, M., Song, Q., Bose, S. J., Calamaio, S., Aston, D., Koschinski, A., Lloyd, S., Bell, L., Rashbrook, V. S., Keller, M., Bracher, F., Potter, B. V., Rivolta, I., Galione, A., Sparrow, D. B., Conti, A., Terrar, D. A., Zaccolo, M., Burton, R. A. B.. 2024-11-26. Lysosomal calcium signalling contributes to the acute α-adrenergic response via calcium-stimulated adenylyl cyclase 1 and 8. https://doi.org/10.1101/2024.11.25.625232

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