Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension
Files
(Published version)
Date
2021
Authors
Grundy, L.
Caldwell, A.
Garcia-Caraballo, S.
Grundy, D.
Spencer, N.J.
Dong, X.
Castro, J.
Harrington, A.M.
Brierley, S.M.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Journal of Neuroscience, 2021; 14(17):3900-3916
Statement of Responsibility
Luke Grundy, Ashlee Caldwell, Sonia Garcia-Caraballo, David Grundy, Nick J. Spencer, Xinzhong Dong ... et al.
Conference Name
Abstract
Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signaling is currently unknown. Using male and female mice, we show with single-cell RT-PCR that subpopulations of DRG neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of coexpression with Trpv1 (81%-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22, and neuropeptide FF) activated subpopulations of bladder-innervating DRG neurons, showing functional evidence of coexpression between MrgprA3, MrgprC11, and TRPV1. In ex vivo bladder-nerve preparations, chloroquine, BAM8-22, and neuropeptide FF all evoked mechanical hypersensitivity in subpopulations (20%-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-clusterD2/2 mice. In vitro whole-cell patch-clamp recordings showed that application of an MrgprA3/C11 agonist mixture induced neuronal hyperexcitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist mixture into the bladder of WT mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of WT, but not Mrgpr-clusterD2/2 mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors triggers hypersensitivity to distension, a critically valuable factor for therapeutic target development.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© 2021 the authors. Authors grant JNeurosci a license to publish their work and copyright remains with the author. For articles published after 2014, the Society for Neuroscience (SfN) retains an exclusive license to publish the article for 6 months; after 6 months, the work becomes available to the public to copy, distribute, or display under the terms of the Creative Commons Attribution 4.0 International License (CC-BY). This license allows data and text mining, use of figures in presentations, and posting the article online, provided that the original article is credited.