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Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_(3A) Receptor Subunit

Bhattacharya, Anindya and Dang, Hong and Zhu, Quan-Ming and Schnegelsberg, Birthe and Rozengurt, Nora and Cain, Gary and Prantil, Rachelle and Vorp, David A. and Guy, Nicholas and Julius, David and Ford, Anthony P. D. W. and Lester, Henry A. and Cockayne, Debra A. (2004) Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_(3A) Receptor Subunit. Journal of Neuroscience, 24 (24). pp. 5537-5548. ISSN 0270-6474. PMCID PMC6729324. doi:10.1523/jneurosci.5658-03.2004.

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Mutant mice with a hypersensitive serotonin (5-HT)_(3A) receptor were generated through targeted exon replacement. A valine to serine mutation (V13′S) in the channel-lining M2 domain of the 5-HT_(3A) receptor subunit rendered the 5-HT₃ receptor ∼70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT_(3B) subunit. Mice homozygous for the mutant allele (5-HT_(3A)^(vs/vs)) had decreased levels of 5-HT_(3A) mRNA. Measurements on sympathetic ganglion cells in these mice showed that whole-cell serotonin responses were reduced, and that the remaining 5-HT₃ receptors were hypersensitive. Male 5-HT_(3A)^(vs/vs) mice died at 2-3 months of age, and heterozygous (5-HT_(3A)^(vs/+)) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT_(3A) mutant mice had urinary bladder mucosal and smooth muscle hyperplasia and hypertrophy, whereas male mutant mice had additional prostatic smooth muscle and urethral hyperplasia. 5-HT_(3A) mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT_(3A)^(vs/vs) mice failed to contract to neurogenic stimulation, despite overall normal responses to a cholinergic agonist, suggestive of altered neuronal signaling in mutant mouse bladders. Consistent with this hypothesis, decreased nerve fiber immunoreactivity was observed in the urinary bladders of 5-HT_(3A)^(vs/vs) compared with 5-HT_(3A) wild-type (5-HT_(3A)^(+/+)) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT_(3A) receptor in vivo may lead to excitotoxic neuronal cell death and functional changes in the urinary bladder, resulting in bladder hyperdistension, urinary retention, and overflow incontinence.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2004 Society for Neuroscience. Received Dec. 22, 2003; revised March 18, 2004; accepted April 22, 2004. This work was supported by National Institutes of Health (NIH) National Research Service Award (H.D.). Funding from NIH Grant NS11756 is gratefully acknowledged. We thank E. Saclolo (Roche), C. Shilyansky, A. Tapper, A. Southwell, and C. Lindsell for help with maintaining the mice.
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Subject Keywords:5-HT3 ; mouse; knock-in mutation; bladder; hypertrophy; afferent innervation
Issue or Number:24
PubMed Central ID:PMC6729324
Record Number:CaltechAUTHORS:20200513-072838651
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Official Citation:Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT3A Receptor Subunit. Anindya Bhattacharya, Hong Dang, Quan-Ming Zhu, Birthe Schnegelsberg, Nora Rozengurt, Gary Cain, Rachelle Prantil, David A. Vorp, Nicholas Guy, David Julius, Anthony P. D. W. Ford, Henry A. Lester, Debra A. Cockayne. Journal of Neuroscience 16 June 2004, 24 (24) 5537-5548; DOI: 10.1523/JNEUROSCI.5658-03.2004
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103163
Deposited By: Tony Diaz
Deposited On:13 May 2020 15:41
Last Modified:16 Nov 2021 18:18

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