title: Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival.
abstract: ATP8A2 is a P4-ATPase that is highly expressed in the retina, brain, spinal cord and testes. In the retina, ATP8A2 is localized in photoreceptors where it uses ATP to transport phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the exoplasmic to the cytoplasmic leaflet of membranes. Although mutations in ATP8A2 have been reported to cause mental retardation in humans and degeneration of spinal motor neurons in mice, the role of ATP8A2 in sensory systems has not been investigated. We have analyzed the retina and cochlea of ATP8A2-deficient mice to determine the role of ATP8A2 in visual and auditory systems. ATP8A2-deficient mice have shortened photoreceptor outer segments, a reduction in photoresponses and decreased photoreceptor viability. The ultrastructure and phagocytosis of the photoreceptor outer segment appeared normal, but the PS and PE compositions were altered and the rhodopsin content was decreased. The auditory brainstem response threshold was significantly higher and degeneration of spiral ganglion cells was apparent. Our studies indicate that ATP8A2 plays a crucial role in photoreceptor and spiral ganglion cell function and survival by maintaining phospholipid composition and contributing to vesicle trafficking.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coleman
authors.forename: Xianjun
authors.initials: X
authors.lastname: Zhu
authors.forename: Hidayat R
authors.initials: HR
authors.lastname: Djajadi
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Molday
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
authors.forename: Robert S
authors.initials: RS
authors.lastname: Molday
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000818:Animals; D002470:Cell Survival; D016057:Evoked Potentials, Auditory, Brain Stem; D006056:Golgi Apparatus / Q000201:enzymology; D006309:Hearing; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055355:Opsins / Q000378:metabolism; D016716:PC12 Cells; D010587:Phagocytosis; D049294:Phospholipid Transfer Proteins / Q000502:physiology*; D010743:Phospholipids / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D055214:Retinal Photoreceptor Cell Outer Segment / Q000502:physiology*; D012243:Rhodopsin / Q000378:metabolism; D013136:Spiral Ganglion / Q000166:cytology*; D022161:Transport Vesicles / Q000378:metabolism; D014785:Vision, Ocular
chemical_list: D008565:Membrane Proteins; D055355:Opsins; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; C571241:TMEM30a protein, mouse; D012243:Rhodopsin; C545446:ATP8a2 protein, mouse; D000251:Adenosine Triphosphatases
keywords: ATP8A2; Auditory system; P4-ATPase; Phospholipid flippase; Photoreceptors; Spiral ganglion cells; Visual system