Reduced phosphatidylinositol 4,5-bisphosphate synthesis impairs inner ear Ca2+ signaling and high-frequency hearing acquisition.
Phosphatidylinositol phosphate kinase type 1γ (PIPKIγ) 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 PIPKIγ(+/-) siblings breed normally and have no reported phenotype. Here we show that adult PIPKIγ(+/-) mice have dramatically elevated hearing thresholds for high-frequency sounds. During the first postnatal week we observed a reduction of ATP-dependent Ca(2+) signaling activity in cochlear nonsensory cells. Because Ca(2+) 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) PIPKIγ 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 PIPKIγ(+/-) mice. This mouse model also suggests that PIPKIγ may determine the level of gap junction contribution to cochlear development.
Istituto Veneto di Medicina Molecolare,  Fondazione per la Ricerca Biomedica Avanzata, 35129 Padua,  Italy.
Laura
L
Rodriguez
Elena
E
Simeonato
Pietro
P
Scimemi
Fabio
F
Anselmi
Bianca
B
Calì
Giulia
G
Crispino
Catalin D
CD
Ciubotaru
Mario
M
Bortolozzi
Fabian Galindo
FG
Ramirez
Paromita
P
Majumder
Edoardo
E
Arslan
Pietro
P
De Camilli
Tullio
T
Pozzan
Fabio
F
Mammano
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000502:physiology*; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D003638:Deafness / Q000235:genetics* / Q000378:metabolism*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000502:physiology; D017629:Gap Junctions / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000378:metabolism; D006309:Hearing / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009925:Organ of Corti / Q000254:growth & development / Q000378:metabolism*; D010641:Phenotype; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D010898:Pitch Perception / Q000502:physiology
D017630:Connexins; D016328:NF-kappa B; D019269:Phosphatidylinositol 4,5-Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase