Nuclear α _1A -Adrenergic Receptor Regulation of cAMP Production by an Inside-Out MAP Kinase Signaling Pathway in Cardiac Myocytes

Sympathetic stimulation produces beneficial changes in cardiac function through β-adrenergic receptor (βAR) production of cAMP and subsequent alteration of electrical and mechanical activity. Long term activation of cAMP production also contributes to cardiac remodeling and detrimental changes associated with heart failure. However, sympathetic responses are mediated by the endogenous neurotransmitter norepinephrine (NE), which is also a potent α ₁ -adrenergic receptor (α ₁ AR) agonist, and α ₁ AR activation can produce significant effects on the heart as well. What is less clear is how α ₁ - and β-adrenergic responses interact with one another. Previous studies have demonstrated that α ₁ AR activation can inhibit β-adrenergic regulation of electrical and mechanical activity of cardiac myocytes, although the signaling mechanisms involved were not previously known. In the present study, we used FRET-based biosensors in adult rat ventricular myocytes to demonstrate that this crosstalk effect involves inhibition of cAMP production by nuclear α _1A ARs acting on βARs found on the plasma membrane. Furthermore, we established that this inside-out signaling mechanism involves a mitogen-activated protein kinase (MAPK) pathway that uncouples βARs from downstream signaling in a G protein coupled receptor kinase (GRK)/arrestin-dependent manner. These results reveal a novel, non-canonical signaling mechanism contributing to α ₁ AR responses in the heart, and that this effect limits βAR production of cAMP by NE. This mechanism may contribute to the cardioprotective effect previously ascribed to α _1A AR activation. These findings also clearly demonstrate the importance of considering the contributions of α ₁ and βARs together when studying the influence of the sympathetic nervous system on the heart.