An Internal Pool of β‐Adrenergic Receptors Activates PLC‐mediated PI4P Hydrolysis in Cardiac Myocytes

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Cardiac hypertrophy and subsequent heart failure is a leading cause of morbidity and mortality in the USA. Previously, our laboratory identified a new prohypertrophic pathway where PLCɛ, scaffolded to mAKAPβ at the nuclear envelope, hydrolyzes phosphatidylinositol 4‐phosphate (PI4P) at the Golgi, locally generating DAG and drive hypertrophic gene expression. This pathway is activated by multiple upstream signals including the Epac‐selective cAMP analogue, cpTOME. However, stimulation of β‐adrenergic receptors with Isoproterenol does not activate this pathway, despite strongly raising cAMP. We were able to uncover Iso stimulated PI4P hydrolysis only in the presence of a cAMP phosphodiesterase 3 inhibitor. Irannejad et al 2 demonstrated that β1‐adrenergic receptors are present in the Golgi membrane of Hela cells and can generate cAMP there. Also, Boivin et al 3 demonstrated that β1‐adrenergic receptors are present in the perinuclear region of adult cardiomyocytes. To determine if internal β‐adrenergic receptors can stimulate PI4P hydrolysis, we treated NRVMs with the membrane permeable β‐adrenergic agonist, dobutamine. In contrast to the membrane impermeable Iso, dobutamine induced rapid and sustained PI4P hydrolysis that was at least partially blocked by the cell permeable β‐adrenergic antagonist, metoprolol (10 μM). The cell impermeable βAR antagonist, sotalol (5 mM) could not block dobutamine effects, suggesting that a pool of internal β‐adrenergic receptors can induce PI4P hydrolysis. Over expression of the RA1 domain of PLCɛ, which competes PLCɛ away from the mAKAPβ scaffold, also inhibited dobutamine stimulation of PI4P hydrolysis. These data suggest that β‐adrenergic stimulation in internal membranes, potentially at the Golgi apparatus or nuclear envelope, can stimulate PI4P hydrolysis. These observations demonstrate a novel mechanism for PLC activation through an internal GPCR which may be responsible for cardiac hypertrophy and heart failure. Targeting internal β‐adrenergic receptors may allow for the development of selective therapies which can treat heart failure with little to no effect on other cardiac functions.Support or Funding InformationThis research was supported by National Institutes of Health Grants R01GM53536 and R01GM81772.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.