Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor

Wei Xu, Shari Gelber, Avi Orr-Urtreger, Dawna Armstrong, Richard A. Lewis, Ching Nan Ou, James Patrick, Lorna Role, Mariella De Biasi, Arthur L. Beaudet

Research output: Contribution to journalArticlepeer-review

Abstract

The α3 subunit of the neuronal nicotinic acetylcholine receptor is widely expressed in autonomic ganglia and in some parts of the brain. The α3 subunit can form heteromultimeric ion channels with other a subunits and with β2 and β4 subunits, but its function in vivo is poorly understood. We prepared a null mutation for the α3 gene by deletion of exon 5 and found that homozygous (-/-) mice lacked detectable mRNA on Northern blotting. The - /- mice survive to birth but have impaired growth and increased mortality before and after weaning. The -/- mice have extreme bladder enlargement, dribbling urination, bladder infection, urinary stones, and widely dilated ocular pupils that do not contract in response to light. Detailed histological studies of -/- mice revealed no significant abnormalities in brain or peripheral tissues except urinary bladder, where inflammation was prominent. Ganglion cells and axons were present in bladder and bowel. Bladder strips from -/- mice failed to contract in response to 0.1 mM nicotine, but did contract in response to electrical field stimulation or carbamoylcholine. The number of acetylcholine-activated single-channel currents was severely reduced in the neurons of superior cervical ganglia in -/- mice with five physiologically distinguishable nicotinic acetylcholine receptor subtypes with different conductance and kinetic properties in wild- type mice, all of which were reduced in -/- mice. The findings in the α3- null mice suggest that this subunit is an essential component of the nicotinic receptors mediating normal function of the autonomic nervous system. The phenotype in -/- mice may be similar to the rare human genetic disorder of megacystis-microcolon-intestinal hypoperistalsis syndrome.

Original languageEnglish
Pages (from-to)5746-5751
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number10
DOIs
StatePublished - 11 May 1999
Externally publishedYes

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