Work

Intracellular α 1A ‐adrenergic receptor regulation of cAMP production by an inside‐out mitogen‐activated protein kinase signalling pathway in cardiac myocytes

Year: 2026

Type: article

Abstract: 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 remodelling 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 the electrical and mechanical activity of cardiac myocytes, although the signalling mechanisms involved were not previously known. In the present study, we used fluorescence resonance energy transfer (FRET)–based biosensors in adult rat ventricular myocytes to demonstrate that this cross‐talk effect involves the inhibition of cAMP production by intracellular α 1A ‐adrenergic receptors (α 1A ARs) acting on βARs found on the plasma membrane. Furthermore, we established that this inside‐out signalling mechanism involves a mitogen‐activated protein kinase (MAPK) pathway that uncouples βARs from downstream signalling in a G protein‐coupled receptor kinase (GRK)/arrestin‐dependent manner. These results reveal a novel, non‐canonical signalling 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. image Key points Acute sympathetic stimulation produces beneficial changes in cardiac function through the release of norepinephrine (NE), activation of β‐adrenergic receptors (βARs) and subsequent production of cAMP. However, long‐term sympathetic stimulation of the same signalling pathway contributes to the development of heart failure and cardiac arrhythmias. NE also activates α 1 ‐adrenergic receptors (α 1 ARs), which have been linked to a cardioprotective effect involving a mechanism not well defined. The present study demonstrates that the activation of intracellular α 1A ‐adrenergic receptors (α 1A ARs) reduces cAMP production by βARs found on the cell surface. This ‘inside‐out’ signalling mechanism acts through a mitogen‐activated protein kinase (MAPK) pathway to enhance β‐arrestin‐mediated uncoupling of βARs from downstream signalling. By limiting excessive cAMP production, α 1A AR signalling may help protect the heart during prolonged sympathetic stimulation, highlighting the importance of considering the effects of α 1 ‐ and βAR signalling together when studying sympathetic responses in the heart.

Source: The Journal of Physiology

DOI: 10.1113/jp290997