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Receptor-like Receptor (receptor-like + receptor)
Selected AbstractsReceptors for calcitonin gene-related peptide and adrenomedullin: implications for skin cell biologyEXPERIMENTAL DERMATOLOGY, Issue 9 2004J. A. Fischer The specificity of a G-protein-coupled calcitonin receptor (CTR) and a CT receptor-like receptor (CLR) for calcitonin gene-related peptide (CGRP), adrenomedullin (AM) and amylin is defined by the heterodimeric non-covalent association with three receptor-activity-modifying proteins (RAMPs). Chemical cross-linking of proteins at the cell surface and immunoprecipitation have identified [125I]CGRP/CLR/RAMP1, [125I]AM/CLR/RAMP2 and -3 as well as [125I]CGRP/CTR/RAMP1, [125I]amylin/CTR/RAMP1 and -RAMP3 complexes. CLR/RAMP1 defines a CGRP receptor. CLR/RAMP2 and -3 correspond to AM1 and AM2 receptor isotypes, respectively. The AM1 receptor cross-reacts with CGRP at high and the AM2 receptor at low concentrations. With the N-terminal deletion of amino acids 14,20 of the mouse, CLR-selective inactivation of AM over CGRP receptor function was obtained. As a result, functional interaction with AM was no longer possible. Overexpression of the CLR in transgenic mice together with the endogenous RAMP2 results in thinning of the hairs during postnatal development (L. M. Ittner et al. conference poster). In conclusion, the extreme N-terminus of the CLR and the extracellular N-terminal domains of RAMP1 and -2 contain amino acid residues that provide AM- or CGRP-binding selectivity of the CLR/RAMP complexes. Hair development is attenuated, resulting in the thinning of the hairs and eventually alopecia during postnatal development. [source] A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of ParkinJOURNAL OF NEUROCHEMISTRY, Issue 6 2006Tomohiro Omura Abstract It has been proposed that in autosomal recessive juvenile parkinsonism (AR-JP), a ubiquitin ligase (E3) Parkin, which is involved in endoplasmic reticulum-associated degradation (ERAD), lacks E3 activity. The resulting accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, leads to endoplasmic reticulum stress, causing neuronal death. We previously reported that human E3 HRD1 in the endoplasmic reticulum protects against endoplasmic reticulum stress-induced apoptosis. This study shows that HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R. Furthermore, the disruption of endogenous HRD1 by small interfering RNA (siRNA) induced Pael-R accumulation and caspase-3 activation. We also found that ATF6 overexpression, which induced HRD1, accelerated and caused Pael-R degradation; the suppression of HRD1 expression by siRNA partially prevents this degradation. These results suggest that in addition to Parkin, HRD1 is also involved in the degradation of Pael-R. [source] Effect of Calcitonin Gene-Related Peptide on Gonadotrophin-Releasing Hormone mRNA Expression in GT1-7 CellsJOURNAL OF NEUROENDOCRINOLOGY, Issue 9 2005J. S. Kinsey-Jones Abstract Recent evidence has shown calcitonin gene-related peptide (CGRP) to be a key mediator of stress-induced suppression of the gonadotrophin-releasing hormone (GnRH) pulse generator, although little is known about the neural pathways involved. In the present study, we investigated the potential direct action of CGRP on GnRH neurones using GT1-7 cells, an established GnRH cell line. First, we detected expression of the CGRP receptor subunits, calcitonin receptor-like receptor and receptor activity-modifying protein-1 in the GT1-7 cells by reverse transcriptase-polymerase chain reaction. Second, we have shown that CGRP inhibits GnRH mRNA expression in the GT1-7 cells, which was effectively reversed by the CGRP receptor antagonist, CGRP8-37. These results suggest that CGRP down regulates expression of GnRH mRNA, via CGRP receptors in the GT1-7 cell, thus implying that a potential direct action of CGRP may mediate a suppressive effect on the GnRH neural network. [source] Noncompetitive antagonism of BIBN4096BS on CGRP-induced responses in human subcutaneous arteriesBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2004Majid Sheykhzade We investigated the antagonistic effect of 1-piperidinecarboxamide, N -[2-[[5amino-l-[[4-(4-pyridinyl)-l-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl) (BIBN4096BS) on the calcitonin gene-related peptide (CGRP)-induced responses by using isometric myograph and FURA-2 technique in human subcutaneous arteries removed in association with abdominal surgery. BIBN4096BS, at the concentration of 1 pM, had no significant effect on the CGRP-induced relaxation in these vessels. At the concentration of 10 pM, BIBN4096BS had a competitive antagonistic-like behaviour characterized by parallel rightward shift in the log CGRP concentration-tension curve with no depression of the Emax. At the higher concentrations (0.1 and 1 nM), BIBN4096BS had a concentration-dependent noncompetitive antagonistic effect on the CGRP-induced responses. The efficacy and potency of CGRP was significantly greater in the smaller (lumen diameter ,200 ,m) human subcutaneous arteries compared to the larger ones. The apparent agonist equilibrium dissociation constant, KA, for CGRP1 receptors in the human subcutaneous arteries was approximately 1 nM. Analysis of the relationship between receptor occupancy and response to CGRP indicates that the receptor reserve is relatively small. Using reverse transcriptase-polymerase chain reaction (RT-PCR), the presence of mRNA sequences encoding the calcitonin receptor-like receptor, receptor activity modifying protein (RAMP1, RAMP2, RAMP3) and receptor component protein were demonstrated in human subcutaneous arteries, indicating the presence of CGRP1 -like receptor and the necessary component for the receptor activation. In conclusion, the inhibitory action of BIBN4096BS at the low concentration (10 pM) on the CGRP-tension curve (but not intracellular calcium concentration ([Ca2+]i) resembles what is seen with a reversible competitive antagonist. However, at the higher concentrations (0.1 and 1 nM), BIBN4096BS acts as a selective noncompetitive inhibitor at CGRP1 receptors in human subcutaneous arteries. British Journal of Pharmacology (2004) 143, 1066,1073. doi:10.1038/sj.bjp.0705967 [source] WHAT MAKES A CGRP2 RECEPTOR?CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2007DL Hay SUMMARY 1Heterogeneity in the receptors for the neuropeptide calcitonin gene-related peptide (CGRP) has been apparent for nearly 20 years. This is most clearly manifested in the observation of CGRP8,37 -sensitive and -insensitive populations of CGRP-activated receptors. The pA2 values for CGRP8,37 in excess of 7 are widely considered to be the result of antagonism of CGRP1 receptors, whereas those below 7 are believed to be the consequence of antagonism of a second population of receptors, namely CGRP2 receptors. 2However, a multitude of pA2 values exist for CGRP8,37, spanning several log units, and as such no obvious clusters of values are apparent. Understanding the molecular nature of the receptors that underlie this phenomenon is likely to aid the development of selective pharmacological tools to progress our understanding of the physiology of CGRP and related peptides. Because there is active development of CGRP agonists and antagonists as therapeutics, such information would also further this pursuit. 3The CGRP1 receptor is pharmacologically and molecularly well defined as a heterodimer of the calcitonin receptor-like receptor (CL) and receptor activity modifying protein (RAMP) 1. The CL/RAMP1 complex is highly sensitive to CGRP8,37. Conversely, the constituents of the CGRP2 receptor have not been identified. In fact, there is little evidence for a distinct molecular entity that represents the CGRP2 receptor. 4Recent pharmacological characterization of receptors related to CGRP1 has revealed that some of these receptors may explain CGRP2 receptor pharmacology. Specifically, AMY1(a) (calcitonin receptor/RAMP1) and AM2 (CL/RAMP3) receptors can be activated by CGRP but are relatively insensitive to CGRP8,37. 5This, along with other supporting data, suggests that the ,CGRP2 receptor' that has been extensively reported in the literature may, in fact, be an amalgamation of contributions from a variety of CGRP-activated receptors. The use of appropriate combinations of agonists and antagonists, along with receptor expression studies, could allow such receptors to be separated. [source] | ||||||||||