期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 35, 页码 14013-14018出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1211869109
关键词
connexins; deafness; phosphoinositides; Ca2+ oscillations; NF-kappa B
资金
- Ministero dell'Istruzione, dell'Universita e della Ricerca-Progetti di Rilevante Interesse Nazionale [2009CCZSES]
- Telethon [GGP09137]
- National Institutes of Health [R37NS036251]
Phosphatidylinositol phosphate kinase type 1 gamma (PIPKI gamma) is a key enzyme in the generation of phosphatidylinositol 4,5-bisphosphate [PI (4,5)P-2] and is expressed at high levels in the nervous system. Homozygous knockout mice lacking this enzyme die postnatally within 24 h, whereas PIPKI gamma(+/-) siblings breed normally and have no reported phenotype. Here we show that adult PIPKI gamma(+/-) mice have dramatically elevated hearing thresholds for high-frequency sounds. During the first postnatal week we observed a reduction of ATP-dependent Ca2+ signaling activity in cochlear nonsensory cells. Because Ca2+ signaling under these conditions depends on inositol-1,4,5-trisphosphate generation from phospholipase C (PLC)-dependent hydrolysis of PI(4,5)P-2, we conclude that (i) PIPKI gamma is primarily responsible for the synthesis of the receptor-regulated PLC-sensitive PI(4,5)P-2 pool in the cell syncytia that supports auditory hair cells; (ii) spatially graded impairment of this signaling pathway in cochlear nonsensory cells causes a selective alteration in the acquisition of hearing in PIPKI gamma(+/-) mice. This mouse model also suggests that PIPKI gamma may determine the level of gap junction contribution to cochlear development.
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