Side” being involved in the pathogenesis of diseases (fibrosis, inflammation, and

Side” being involved in the NSC 697286 web pathogenesis of diseases (fibrosis, inflammation, and cancer, among many others); at the cellular level, it modulates migration, chemotaxis, proliferation, survival, and other processes (see [1?] and references therein). LPA actions are mainly exerted through a family of G protein-coupled receptors (GPCRs), that is, the LPA receptors, comprising six members that are currently designated LPA1?; the possibility that GPR87 could be also a member of this family has been suggested, i. e., such as LPA7 [1?]. Of jasp.12117 these receptors, LPA1, LPA2 and LPA3 are phylogenetically related among themselves and also with those of other bioactive lipids (the endothelial differentiation gene [“edg”] family); the remaining LPA receptors are distant phylogenetically from these and are more closely related with the purinergic receptor family [1?]. Evolutionary aspects of these receptors, among vertebrates, have been recently reported [7]. It is also known that LPA can modulate transcription through nuclear receptors, such as the peroxisome proliferator-activated receptor [8]. LPA also activates the TRPV1 ion channel involved in the control of body temperature and nociception [9]. Our present work deals exclusively with the LPA1? receptors. The actions of these receptors have been studied using many different natural (i. e. endogenously expressed) and transfected cellular and systemic models. However, few studies have analyzed LPA1? desensitization and internalization employing the same cellular model. In particular, the phosphorylation of these receptors has been scarcely studied. To the best of our knowledge, solely LPA1 receptor phosphorylation has been reported and only by our own group [4, 10?4]. The present work was designed to fulfill this gap in knowledge. Desensitization, defined as a stage of reduced BL-8040 price sensitivity to a particular stimulus, can involve a large number of processes with different time scales. It is generally accepted that GPCR sensitivity (desensitization/ resensitization) involves phosphorylation/ dephosphorylation cycles controlled by particular protein kinases and phosphatases wcs.1183 [15?0]; although there is evidence also for phosphorylation-independent desensitization [21]. The majority of current data indicate that agonist-induced receptor desensitization (homologous desensitization) involves receptor phosphorylation by G protein-coupled receptor kinases (GRKs) whereas desensitization of unoccupied receptors, i. e. agonist-independent (heterologous desensitization) mainly involves signaling activated kinases such as the second messenger-activated kinases, protein kinase A and protein kinase C (PKC), among others [15?0]. Receptor internalization appears to be related with receptor phosphorylation. Current ideas indicate that phosphorylated receptors interact with -arrestins and act as molecular bridges with clathrin, clustering receptors that internalize in coated vesicles; such internalization can lead receptors to plasma membrane recycling, trafficking to other compartments or to degradation. Variation in the phosphorylation pattern of a given receptor has been observed and it has been suggested that such phosphorylation “bar code” might determine receptor’s destination and function [19, 22, 23]. Recently, we reported differential association of 1B-adrenergic receptors to Rab proteins during internalizations induced by agonists (homologous) or unrelated (heterologous) stimuli [24]. In silico analysis showed that.Side” being involved in the pathogenesis of diseases (fibrosis, inflammation, and cancer, among many others); at the cellular level, it modulates migration, chemotaxis, proliferation, survival, and other processes (see [1?] and references therein). LPA actions are mainly exerted through a family of G protein-coupled receptors (GPCRs), that is, the LPA receptors, comprising six members that are currently designated LPA1?; the possibility that GPR87 could be also a member of this family has been suggested, i. e., such as LPA7 [1?]. Of jasp.12117 these receptors, LPA1, LPA2 and LPA3 are phylogenetically related among themselves and also with those of other bioactive lipids (the endothelial differentiation gene [“edg”] family); the remaining LPA receptors are distant phylogenetically from these and are more closely related with the purinergic receptor family [1?]. Evolutionary aspects of these receptors, among vertebrates, have been recently reported [7]. It is also known that LPA can modulate transcription through nuclear receptors, such as the peroxisome proliferator-activated receptor [8]. LPA also activates the TRPV1 ion channel involved in the control of body temperature and nociception [9]. Our present work deals exclusively with the LPA1? receptors. The actions of these receptors have been studied using many different natural (i. e. endogenously expressed) and transfected cellular and systemic models. However, few studies have analyzed LPA1? desensitization and internalization employing the same cellular model. In particular, the phosphorylation of these receptors has been scarcely studied. To the best of our knowledge, solely LPA1 receptor phosphorylation has been reported and only by our own group [4, 10?4]. The present work was designed to fulfill this gap in knowledge. Desensitization, defined as a stage of reduced sensitivity to a particular stimulus, can involve a large number of processes with different time scales. It is generally accepted that GPCR sensitivity (desensitization/ resensitization) involves phosphorylation/ dephosphorylation cycles controlled by particular protein kinases and phosphatases wcs.1183 [15?0]; although there is evidence also for phosphorylation-independent desensitization [21]. The majority of current data indicate that agonist-induced receptor desensitization (homologous desensitization) involves receptor phosphorylation by G protein-coupled receptor kinases (GRKs) whereas desensitization of unoccupied receptors, i. e. agonist-independent (heterologous desensitization) mainly involves signaling activated kinases such as the second messenger-activated kinases, protein kinase A and protein kinase C (PKC), among others [15?0]. Receptor internalization appears to be related with receptor phosphorylation. Current ideas indicate that phosphorylated receptors interact with -arrestins and act as molecular bridges with clathrin, clustering receptors that internalize in coated vesicles; such internalization can lead receptors to plasma membrane recycling, trafficking to other compartments or to degradation. Variation in the phosphorylation pattern of a given receptor has been observed and it has been suggested that such phosphorylation “bar code” might determine receptor’s destination and function [19, 22, 23]. Recently, we reported differential association of 1B-adrenergic receptors to Rab proteins during internalizations induced by agonists (homologous) or unrelated (heterologous) stimuli [24]. In silico analysis showed that.

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