Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance

Abstract

Adrenergic receptors (AR) are G-protein-coupled receptors (GPCRs) that have a crucial role in cardiac physiology in health and disease. Alpha1-ARs signal through Gαq, and signaling through Gq, for example, by endothelin and angiotensin receptors, is thought to be detrimental to the heart. In contrast, cardiac alpha1-ARs mediate important protective and adaptive functions in the heart, although alpha1-ARs are only a minor fraction of total cardiac ARs. Cardiac alpha1-ARs activate pleiotropic downstream signaling to prevent pathologic remodeling in heart failure. Mechanisms defined in animal and cell models include activation of adaptive hypertrophy, prevention of cardiac myocyte death, augmentation of contractility, and induction of ischemic preconditioning. Surprisingly, at the molecular level, alpha1-ARs localize to and signal at the nucleus in cardiac myocytes, and, unlike most GPCRs, activate "inside-out" signaling to cause cardioprotection. Contrary to past opinion, human cardiac alpha1-AR expression is similar to that in the mouse, where alpha1-AR effects are seen most convincingly in knockout models. Human clinical studies show that alpha1-blockade worsens heart failure in hypertension and does not improve outcomes in heart failure, implying a cardioprotective role for human alpha1-ARs. In summary, these findings identify novel functional and mechanistic aspects of cardiac alpha1-AR function and suggest that activation of cardiac alpha1-AR might be a viable therapeutic strategy in heart failure.

Figures

Fig. 1.

Model for α1-AR signaling at the nuclear membrane. In adult cardiac myocytes, catecholamine α1-AR agonists (NE/PE) are actively transported into the myocyte via organic cation transporter 3 (OCT), which can be inhibited by corticosterone. The membrane-permeable α1-AR antagonist prazosin (and similar derivatives) can cross the plasma membrane to inhibit signaling, whereas the membrane impermeable α1-AR antagonist CGP12177A fails to inhibit signaling. The model suggests that active α1-ARs localize to the inner nuclear membrane with the ligand-binding domain facing the space between the outer and inner nuclear membranes (ONM and INM, respectively). On the basis of this orientation, binding of agonist to α1-ARs induces signaling inside the nucleus, possibly through Gαq, although downstream intranuclear signaling pathways remain to be defined. We propose that activation of nuclear α1-ARs can induce intranuclear hypertrophic signaling as well as extranuclear signaling, including activation of ERK in caveolae and survival signaling or phosphorylation of cardiac troponin I at the sarcomere and contractile function. HDAC, histone deacetylase; Ca Ch, calcium channel; RYR, ryanodine receptor; PTP, mitochondrial permeability transition pore; ER/SR, endoplasmic/ sarcoplasmic reticulum; NR, nucleoplasmic reticulum; NPC, nuclear pore complex.