Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension

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dc.contributor.authorGrundy, L.
dc.contributor.authorCaldwell, A.
dc.contributor.authorGarcia-Caraballo, S.
dc.contributor.authorGrundy, D.
dc.contributor.authorSpencer, N.J.
dc.contributor.authorDong, X.
dc.contributor.authorCastro, J.
dc.contributor.authorHarrington, A.M.
dc.contributor.authorBrierley, S.M.
dc.date.issued2021
dc.description.abstractUnderstanding 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.
dc.description.statementofresponsibilityLuke Grundy, Ashlee Caldwell, Sonia Garcia-Caraballo, David Grundy, Nick J. Spencer, Xinzhong Dong ... et al.
dc.identifier.citationJournal of Neuroscience, 2021; 14(17):3900-3916
dc.identifier.doi10.1523/jneurosci.0033-21.2021
dc.identifier.issn0270-6474
dc.identifier.issn1529-2401
dc.identifier.orcidCastro, J. [0000-0002-5781-2224]
dc.identifier.orcidHarrington, A.M. [0000-0002-1562-4137]
dc.identifier.orcidBrierley, S.M. [0000-0002-2527-2905]
dc.identifier.urihttp://hdl.handle.net/2440/131004
dc.language.isoen
dc.publisherSociety for Neuroscience
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1140297
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1126378
dc.relation.granthttp://purl.org/au-research/grants/arc/DP180101395
dc.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.
dc.source.urihttps://doi.org/10.1523/jneurosci.0033-21.2021
dc.subjectBladder; GPCR; itch; pain; sensory neurons; visceral afferents
dc.titleActivation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension
dc.typeJournal article
pubs.publication-statusPublished

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