Calcium-dependent signaling by adrenergic receptors

Calcium-dependent signaling by adrenergic receptors

Calcium is also involved in the cellular effects of media-tors such as epinephrine and norepinephrine. In the heart, the predominant adrenergic receptors are of the type β₁, and both agonists and antagonists of β receptors are being used in cardiac therapy. β-Adrenoceptors always activate adenylate cyclase and, through cAMP, protein kinase A (PKA). However, the downstream effectors may differ de-pending on the cell type. In the heart, PKA changes the ac-tivity of several target proteins including RyR, DHPR, and the regulatory ER membrane protein phospholamban (Fig-ure 6.10a). While the effect of phospholamban phosphory-lation is a disinhibition of SERCA (SR/ER calcium trans-porter, an ATP-dependent uniporter) that will tend to reduce cytosolic Ca⁺⁺, the first two will increase the availability of Ca⁺⁺, which seems to be the net effect.

In smooth muscle, contraction is slower and longer lasting than in striated muscle. Regulation of actin and myosin does not work by way of troponin / tropomyosin but by phosphorylation of the regulatory myosin light chain (Fig-ure 6.10b). This is catalyzed by myosin light chain kinase (MLCK), which is calmodulin-dependent and, hence, again under the control of calcium. However, less calcium is nec essary in this regulatory mechanism, because MLCK pro-vides an extra amplification stage not present in the direct binding of calcium to troponin.

In smooth muscle, β-adrenoceptors decrease contractility: PKA phosphorylates MLCK, which thereby becomes in-activated. In contrast, α₁-adrenoceptors increase smooth muscle contractility. They activate phospholipase C, which in turn releases inositoltriphosphate (IP₃) from the endo-plasmic reticulum by binding to a cognate receptor chan-nel (Figure 6.10c). Ca⁺⁺ then binds to calmodulin, which in turn activates myosin light chain kinase.