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The Journal of Neuroscience, June 16, 2004, 24(24):5537-5548; doi:10.1523/JNEUROSCI.5658-03.2004

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Cellular/Molecular
Uropathic Observations in Mice Expressing a Constitutively Active Point Mutation in the 5-HT_3A Receptor Subunit

Anindya Bhattacharya,¹ Hong Dang,² Quan-Ming Zhu,¹ Birthe Schnegelsberg,¹ Nora Rozengurt,³ Gary Cain,¹ Rachelle Prantil,⁴ David A. Vorp,⁴ Nicholas Guy,⁵ David Julius,⁵ Anthony P. D. W. Ford,¹ Henry A. Lester,² and Debra A. Cockayne¹

¹Roche Pharmaceuticals, Palo Alto, California 94304, ²Caltech, Pasadena, California 91125, ³Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, ⁴Departments of Surgery and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and ⁵Department of Cell and Molecular Pharmacology, University of California San Francisco, San Francisco, California 94143

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.

Key words: 5-HT₃; mouse; knock-in mutation; bladder; hypertrophy; afferent innervation

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Received Dec 22, 2003; revised March 18, 2004; accepted April 22, 2004.

This article has been cited by other articles:

				X.-Q. Hu and R. W. Peoples The 5-HT3B Subunit Confers Spontaneous Channel Opening and Altered Ligand Properties of the 5-HT3 Receptor J. Biol. Chem., March 14, 2008; 283(11): 6826 - 6831. [Abstract] [Full Text] [PDF]

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