Tissue-specific adrenergic regulation of the L-type Ca2+ channel CaV1.2

Abstract

Ca²⁺ influx through the L-type Ca²⁺ channel Cav1.2 triggers each heartbeat. The fight-or-flight response induces the release of the stress response hormone norepinephrine to stimulate β-adrenergic receptors, cAMP production, and protein kinase A activity to augment Ca²⁺ influx through Ca_v1.2 and, consequently, cardiomyocyte contractility. Emerging evidence shows that Ca_v1.2 is regulated by different mechanisms in cardiomyocytes compared to neurons and vascular smooth muscle cells.

Figure 1:. Differential regulation of Cav1.2 by β AR stimulation in neurons and cardiomyocytes.

Models depict the hypothesized overall structural arrangements of part of the β₂ AR/Cav1.2 signaling complex as might be prevalent in neurons (left) and cardiomyocytes (right). Cav1.2 is thought to mostly reside outside lipid rafts in neurons (darker membrane) and in lipid rafts in cardiomyocytes (lighter membrane) (22, 23). Rad is present predominantly in cardiomyocytes and might bind to the β subunit and the N-terminus and PCT of the α₁ subunit of Cav1.2, either through multiple interactions as depicted or in multiple copies (not depicted). AKAP150 and AKAP15 seem to be the predominant AKAP in neurons and cardiomyocytes, respectively. AKAP150 links both adenylyl cyclase and PKA to Cav1.2 and has multiple interaction sites with Cav1.2 (15). AKAP15 is shorter than AKAP150 and may link only PKA to Cav1.2. How AC is linked to Cav1.2 when AKAP15 is in the Cav1.2 complex is unclear. The PCT and DCT are depicted in a ‘closed’ conformation in the left model due to salt bridges between Arg¹⁶⁹⁶ and Arg¹⁶⁹⁷ in the PCT and Glu²¹⁰³, Glu²¹⁰⁶ and Asp²¹¹⁰ in the DCT and in an ‘open’ conformation in the right model, perhaps due to differences in the environment of Cav1.2 (inside compared to outside of rafts) or associated proteins. Arg¹⁶⁹⁶ and Arg¹⁶⁹⁷ are part of the PKA consensus site for phosphorylation of Ser¹⁷⁰⁰, which disrupts these salt bridges. Ser¹⁹²⁸ is the main PKA phosphorylation site in α₁1.2. For simplicity, the linkers between the transmembrane segments of the α₁ subunit of Cav1.2 are not shown.

Figure 2:. Antagonistic effects of Rem and α-actinin on Cav1.2.

Schematic depiction of α-actinin promoting (green arrows) and Rem antagonizing (red lines) three major parameters that affect Cav1.2 functions: surface abundance, movement of the voltage sensing S4 transmembrane helices, which carry the gating charges, and coupling of gating movements to pore opening. Impaired coupling has been directly determined for loss of α-actinin binding to Cav1.2 (36) and is suggested by analogy for Rem binding (31, 33). For simplicity, the linkers between the transmembrane segments of the α₁ subunit of Cav1.2 are not shown.