Rabbit Anti-Human CALCRL (internal) Polyclonal antibody

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disease for which there is currently no effective treatment. The progression of ALS includes loss of motor neurons controlling the voluntary muscles, with much of this loss occurring at the neuromuscular junction. In an effort to better understand changes at the neuromuscular junction, we utilized the wobbler mouse model of motor neuron loss. We examined biceps and end plate morphologies and monitored selected factors involved in end plate function. Structural volumes were determined from 3D reconstructions that were generated for the end plates. Wobbler mice exhibited size reductions of both the muscle fibers and the end plates within the biceps, and we found that the end plate volumes were the most sensitive indicator of the degeneration. Concurrently, we found increases in calcitonin gene-related peptide (CGRP) and its receptor in wobbler biceps and spinal cord. We also found increases in gene expression of two acetylcholine receptors within the wobbler biceps, which may be a result of altered CGRP/CALCRL (calcitonin receptor-like receptor) expression.

The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating G alpha q- and beta-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as G alpha s in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, G alpha s signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to G alpha s/cAMP signaling in the same ovarian carcinoma-derived cell line. G alpha s/cAMP/PKA activation inhibits ETAR-mediated beta-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, G alpha s overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for G alpha s signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates G alpha s-coupled tumor suppressive pathways while blocking G alpha q-/beta-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC. (C) 2014 Elsevier Inc. All rights reserved.