High Blood Pressure / Hypertension

β-Adrenergic System

By Cardiologist on December 23rd, 2011

Desensitization, internalization and recycling of β-adrenergic receptors

Desensitization, internalization and recycling of β-adrenergic receptors

Activation of β-adrenergic receptors causes their phosphorylation by members of the GRKs. Cytosolic β-arrestins then bind to the phosphorylated receptors and prevent further interaction with G-proteins. β-Arrestin-bound receptors assemble in clathrin-coated pits, where the complex appears to interact with other proteins, including dynamin and src-kinase. This leads (i) to the activation of non-conventional signalling pathways (raf-kinases, MAP-kinases, JNK-kinases), and (ii) to the internalization of the receptors to endosomes. Endosomal receptors become either dephosphorylated and recycle back to the cell surface; some endosomal receptors undergo lysosomal degradation.

β-Adrenergic signalling in cardiac muscle (predominantly β1) and smooth muscle (predominantly β₂) cells

β-Adrenergic signalling in cardiac muscle

β-Adrenergic signalling in cardiac muscle (predominantly β1) and smooth muscle (predominantly β₂) cells. Proteins that become more active after activation of β-adrenergic receptors are depicted in grey, those which become less active are depicted in white. Both receptors couple to G_s and lead to activation of adenylyl cyclases, generation of cyclic AMP and activation or protein kinase A (protein kinase A). In heart muscle cells, protein kinase A causes phosphorylation of L-type calcium channels (increased Ca²⁺-influx; relevant site of phosphorylation uncertain), troponin I (Tnl; diminishes affinity of troponin C for Ca²⁺ and thus enhances relaxation) and phospholamban (PLB; leads to less inhibition of the sarcoplasmic Ca²⁺ ATPase, SERCA, which pumps Ca²⁺into the sarcoplasmic stores. This in turn enhances relaxation and enhances Ca²⁺-release during the next beat) All this leads to more rapid and forceful contraction as well as relaxation. In smooth muscle cell the signalling pathways are less clear protein kinase A-mediated phosphorylation of myosin light chain kinase (MLCK) causes reduced activity of this kinase, which in turn leads to decreased phosphorylation of myosin light chains and, hence, reduced contraction. A second postulated mechanism for relaxation is hyperpolarization via activation of K⁺-channels; the signalling pathway is unclear and might involve coupling of β₂-receptors to G1.

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