P-adrenergic receptor kinase

PARK p-adrenergic receptor kinase CIDP chronic inflammatory demyelinating polyneuropathy... 

Fig. 5.9. Receptor desensitization translocation and arrestin binding. The Py-complex released on activation of the G-protein associates with the P-adrenergic receptor kinase (PARK) and rec-rnits this to the membrane. Consequently, the PARK phosphorylates the activated P-receptor and removes it from the signal chain. Arrestin binds to the phosphorylated receptor. In the arrestin-bound form, the signal can no longer be transmitted to the G-protein and signal conduction is disrupted. The phosphorylated receptor is transported in the form of vesicles into the cell interior (internahzation) and, after dephosphorylation, is returned to the membrane (recycling).

The interaction of the Pycomplex with G-protein coupled receptor kinases (see 5.3.4, P-adrenergic receptor kinase, PARK) appears to be of special regulatory importance. The function of the Py-complex in this system is shown in Fig. 5.9. The Py-complex binds specifically to the PARK and translocates this to the cell membrane. The translocation of PARK is necessary to switch off and modulate signal transmission via adrenaline. 

Serpentine receptor kinase P-adrenergic receptor kinase, PARK... 

Rockman, H.A., Chien, K.R., Choi, D.J., Iaccarino, G., Hunter, J.J., Ross, J., Jr., Lefkowitz, R.J., and Koch, WJ. 1998. Expression of a p-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc. Natl. Acad. Sci. USA 95 7000-7005. 

Desensitization of receptors Prolonged exposure to the catecholamines reduces the responsivity of these receptors, a phenomenon known as desensitization. Three mechanisms have been suggested to explain this phenomenon (1) sequestration of the receptors so that they are unavailable for interaction with the ligand (2) down-regulation, that is, a disappearance of the receptor either by destruction or decreased synthesis and (3) inability to couple to G-protein because the receptor has been phosphory-lated on the cytoplasmic side by either protein kinase A or p adrenergic receptor kinase (PARK). 

Fig. 5.5 Desensitization of the activated (Tadrenergic receptor, PAR. PARK is the p-adrenergic receptor kinase, as and py are the activated a-subunit and the Py-subunits of the heterotrimeric G protein, Gg. AC is the activated effector, the enzyme adenylyl cyclase. Phosphorylation of activated GPCRs enhances binding of a family of proteins, the arrestins, which prevent access of G proteins and uncouple the receptor from G proteins. The arrestin involved in the desensitization of the P-adrenergic receptor is p-arrestin. (Reproduction of this scheme has been made possible through the generosity of Professor Martin Lohse, Department of Pharmacology, University of Wurzburg, Medical School.)...

Benovic JL, Kuhn H, Weyand I, Codina J, Caron MG, Lefkowitz RJ. Functional desensitization of the isolated P-adrenergic receptor by the P-adrenergic receptor kinase potential role of an analog of the retinal protein arrestin (48-kDa protein). Proc Natl Acad Sci USA 1987 84 8879-8882. 

Fig. 2. Major mechanisms involved in [i-AR desensitization and internalization. AP2, adaptor protein 2 p-ARK, P-adrenergic receptor kinase PI3K, phosphatidylinositol-3 kinase PIP3, phosphatidyl-inositol-3,4,5-triphosphate. (See Color Plate 3 following p. 148.)...

Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of P-adrenergic receptor kinase and P,-adrenergic receptors in the failing human heart. Circulation 1993 87 454 163. 

Petrofski JA, Koch WJ. The p-adrenergic receptor kinase in heart failure. J Mol Cell Cardiol 2003 35 1167-1174. 

Koch WJ, Rockman HA, Samama P, et al. Cardiac function in mice overexpressing the p-adrenergic receptor kinase or a PARK inhibitor. Science 1995 268 1350-1353. 

Shah AS, White DC, Emani S, et al. In vivo ventricular gene delivery of a p-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 2001 103 1311-1316. 

Tevaearai HT, Eckhart AD, Shotwell KF, Wilson K, Koch WJ. Ventricular dysfunction after cardioplegic arrest is improved after myocardial gene transfer of a p-adrenergic receptor kinase inhibitor. Circulation 2001 104 2069-2074. 

The p-adrenergic receptor system comprises the main membrane-bound components of transmembrane signaling, which are the receptors themselves, the G-proteins Gg, and adenylyl cyclases. In addition, the receptor system contains several cytosolic proteins which regulate the signaling process (Figure 1). The most important ones of these are the p-adrenergic receptor kinases and the... 

The abbreviations denote pAR, P-adrenergic receptor PARK, P-adrenergic receptor kinase AC, adenylyl cyclase PKA, protein kinase A PhD, phosducin. 

P-adrenergic receptor kinase, P-ARK phosducin regulators of G protein signaling, RGS PI3-kinase type y... 

Fig. 4.10. P-Adrenoceptor regulation. Following repeated stimulation of the P-adrenoceptor by an agonist, phosphorylation of amino acids on the intracellular C-terminal domain by protein kinase A (PKA) and/or P-adrenergic receptor kinase (PARK) may (A) prevent subsequent G-protein binding, (B) enhance removal of the receptor from the membrane via sequestration into endosomes, or (C) enhance degradation via lysosomal internalization and cleavage.

Like other G-protein-coupled receptors, the N-formyl peptide receptor can be phosphorylated [8, 382], and neutrophils have a G-protein-coupled receptor kinase GRK2 (also known as P-adrenergic receptor kinase) [61, 312], Phosphorylation of the N-formyl peptide receptor in HL-60... 

Chuang, T.T., Sallese, M., Ambrosini, G., Pamiti, G. and De Blasi, A. (1992). High expression of P-adrenergic receptor kinase in human peripheral blood leukocytes. J. Biol. Chem. 267, 6886-6892. 

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