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10.1073/pnas.1706656114 http://scihub22266oqcxt.onion/10.1073/pnas.1706656114 C5699040!5699040 !29087309     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\29087309 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Proc+Natl+Acad+Sci+U+S+A 2017 ; 114 (46 ): 12309-12314 Nephropedia Template TP {{tp|p=29087309 |t=2017. Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission |pdf=|usr=}}{{29087309 }} gab.com Text Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission JO: Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=29087309 #FOAvip G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP(8-37), accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP(8-37)-cholestanol, but not unconjugated CGRP(8-37), prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP(8-37)-cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund's adjuvant more effectively than unconjugated CGRP(8-37) Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention. Twit Text FOAVip Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission ????Proc Natl Acad Sci U S A http://www.kidney.de/pget.php?&tw=1&pmid=29087309 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29087309 #FOAvip English Wikipedia <ref>{{Cite pmid|29087309 }}</ref> Endosomal signaling of the receptor for calcitonin gene-related peptide mediates pain transmission #MMPMID29087309 Yarwood RE ; Imlach WL ; Lieu T ; Veldhuis NA ; Jensen DD ; Klein Herenbrink C ; Aurelio L ; Cai Z ; Christie MJ ; Poole DP ; Porter CJH ; McLean P ; Hicks GA ; Geppetti P ; Halls ML ; Canals M ; Bunnett NW Proc Natl Acad Sci U S A 2017[Nov]; 114 (46 ): 12309-12314 PMID29087309 show ga G protein-coupled receptors (GPCRs) are considered to function primarily at the plasma membrane, where they interact with extracellular ligands and couple to G proteins that transmit intracellular signals. Consequently, therapeutic drugs are designed to target GPCRs at the plasma membrane. Activated GPCRs undergo clathrin-dependent endocytosis. Whether GPCRs in endosomes control pathophysiological processes in vivo and are therapeutic targets remains uncertain. We investigated the contribution of endosomal signaling of the calcitonin receptor-like receptor (CLR) to pain transmission. Calcitonin gene-related peptide (CGRP) stimulated CLR endocytosis and activated protein kinase C (PKC) in the cytosol and extracellular signal regulated kinase (ERK) in the cytosol and nucleus. Inhibitors of clathrin and dynamin prevented CLR endocytosis and activation of cytosolic PKC and nuclear ERK, which derive from endosomal CLR. A cholestanol-conjugated antagonist, CGRP(8-37), accumulated in CLR-containing endosomes and selectively inhibited CLR signaling in endosomes. CGRP caused sustained excitation of neurons in slices of rat spinal cord. Inhibitors of dynamin, ERK, and PKC suppressed persistent neuronal excitation. CGRP(8-37)-cholestanol, but not unconjugated CGRP(8-37), prevented sustained neuronal excitation. When injected intrathecally to mice, CGRP(8-37)-cholestanol inhibited nociceptive responses to intraplantar injection of capsaicin, formalin, or complete Freund's adjuvant more effectively than unconjugated CGRP(8-37) Our results show that CLR signals from endosomes to control pain transmission and identify CLR in endosomes as a therapeutic target for pain. Thus, GPCRs function not only at the plasma membrane but also in endosomes to control complex processes in vivo. Endosomal GPCRs are a drug target that deserve further attention. |Adrenergic Antagonists/pharmacology [MESH] |Animals [MESH] |Calcitonin Gene-Related Peptide/pharmacology [MESH] |Calcitonin Receptor-Like Protein/antagonists & inhibitors/*genetics/metabolism [MESH] |Capsaicin/antagonists & inhibitors/pharmacology [MESH] |Cholestanols/pharmacology [MESH] |Clathrin/antagonists & inhibitors/genetics/metabolism [MESH] |Dynamins/genetics/metabolism [MESH] |Endocytosis/*drug effects [MESH] |Endosomes/drug effects/*metabolism [MESH] |Formaldehyde/antagonists & inhibitors/pharmacology [MESH] |Freund's Adjuvant/antagonists & inhibitors/pharmacology [MESH] |Gene Expression Regulation [MESH] |Injections, Spinal [MESH] |Male [MESH] |Mice [MESH] |Microtomy [MESH] |Mitogen-Activated Protein Kinase 1/genetics/metabolism [MESH] |Mitogen-Activated Protein Kinase 3/genetics/metabolism [MESH] |Nociception/drug effects/*physiology [MESH] |Pain/chemically induced/genetics/*physiopathology/prevention & control [MESH] |Peptide Fragments/pharmacology [MESH] |Protein Kinase C/genetics/metabolism [MESH] |Rats [MESH] |Spinal Cord/cytology/drug effects/metabolism [MESH] |Synaptic Transmission/*drug effects [MESH]Endosomal signaling of the receptor for calcitonin gene-related peptid(epmc).pdf DeepDyve Pubget Overpricing