Uropathic observations in mice expressing a constitutively active point mutation in the 5-HT3A receptor subunit.
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-HT3A receptor subunit rendered the 5-HT3 receptor 70-fold more sensitive to serotonin and produced constitutive activity when combined with the 5-HT3B subunit. Mice homozygous for the mutant allele (5-HT3Avs/vs) had decreased levels of 5-HT3A 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-HT3Avs/vs mice died at 2-3 months of age, and heterozygous (5-HT3Avs/+) males and homozygous mutant females died at 4-6 months of age from an obstructive uropathy. Both male and female 5-HT3A 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-HT3A mutant mice had marked voiding dysfunction characterized by a loss of micturition contractions with overflow incontinence. Detrusor strips from 5-HT3Avs/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-HT3Avs/vs compared with 5-HT3A wild-type (5-HT3A+/+) mice. These data suggest that persistent activation of the hypersensitive and constitutively active 5-HT3A 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.
Bhattacharya
Anindya
A
Roche Pharmaceuticals, Palo Alto, California 94304, USA.
Dang
Hong
H
Zhu
Quan-Ming
QM
Schnegelsberg
Birthe
B
Rozengurt
Nora
N
Cain
Gary
G
Prantil
Rachelle
R
Vorp
David A
DA
Guy
Nicholas
N
Julius
David
D
Ford
Anthony P D W
AP
Lester
Henry A
HA
Cockayne
Debra A
DA
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009130:Muscle, Smooth / Q000503:physiopathology; D009412:Nerve Fibers / Q000473:pathology; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D044406:Receptors, Serotonin, 5-HT3 / Q000096:biosynthesis* / Q000235:genetics*; D014521:Urethra / Q000503:physiopathology; D001743:Urinary Bladder / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D001748:Urinary Bladder Neck Obstruction / Q000401:mortality / Q000473:pathology* / Q000503:physiopathology*; D014563:Urodynamics; D014981:Xenopus
D044406:Receptors, Serotonin, 5-HT3