Cardiac contraction and relaxation are regulated by distinct subcellular cAMP pools

• Published in: Nature chemical biology Vol. 20; no. 1; pp. 62 - 73
• Main Authors: Lin, Ting-Yu, Mai, Quynh N., Zhang, Hao, Wilson, Emily, Chien, Huan-Chieh, Yee, Sook Wah, Giacomini, Kathleen M., Olgin, Jeffrey E., Irannejad, Roshanak
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-01-2024; Nature Publishing Group
• Subjects: 631/136/334/1874; 631/443/592/75; 631/80/86; 631/92/612/194; 631/92/96; Adenosine; Adenosine monophosphate; Adrenergic receptors; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cardiomyocytes; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cyclic AMP; Danio rerio; G protein-coupled receptors; Golgi apparatus; Heart; Kinases; Membranes; Muscle contraction; Physiological responses; Physiology; Protein kinase A; Proteins; Receptors (physiology); Second messengers; Zebrafish
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-023-01381-8

Cells interpret a variety of signals through G-protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to the regulation of a specific protein kinase A (PKA) target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.
A pivotal role for beta-1 adrenergic receptor (β1AR) subcellular signaling in controlling cardiac relaxation response through the generation of cyclic adenosine monophosphate (cAMP) and activation of local protein kinase A (PKA) effectors was revealed in cardiomyocytes and in intact zebrafish and mice hearts.