Reduced electromotility of outer hair cells associated with connexin-related forms of deafness: an in silico study of a cochlear network mechanism.
J Assoc Res Otolaryngol
; 11(4): 559-71, 2010 Dec.
Article
en En
| MEDLINE
| ID: mdl-20635191
ABSTRACT
Mutations in the GJB2 gene encoding for the connexin 26 (Cx26) protein are the most common source of nonsyndromic forms of deafness. Cx26 is a building block of gap junctions (GJs) which establish electrical connectivity in distinct cochlear compartments by allowing intercellular ionic (and metabolic) exchange. Animal models of the Cx26 deficiency in the organ of Corti seem to suggest that the hearing loss and the degeneration of outer hair cells (OHCs) and inner hair cells is due to failed K(+) and metabolite homeostasis. However, OHCs can develop normally in some mutants, suggesting that the hair cells death is not the universal mechanism. In search for alternatives, we have developed an in silico large scale three-dimensional model of electrical current flow in the cochlea in the small signal, linearised, regime. The effect of mutations was analysed by varying the magnitude of resistive components representing the GJ network in the organ of Corti. The simulations indeed show that reduced GJ conductivity increases the attenuation of the OHC transmembrane potential at frequencies above 5 kHz from 6.1 dB/decade in the wild-type to 14.2 dB/decade. As a consequence of increased GJ electrical filtering, the OHC transmembrane potential is reduced by up to 35 dB at frequencies >10 kHz. OHC electromotility, driven by this potential, is crucial for sound amplification, cochlear sensitivity and frequency selectivity. Therefore, we conclude that reduced OHC electromotility may represent an additional mechanism underlying deafness in the presence of Cx26 mutations and may explain lowered OHC functionality in particular reported Cx26 mutants.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Silicio
/
Movimiento Celular
/
Cóclea
/
Células Ciliadas Auditivas Externas
/
Conexinas
/
Sordera
/
Modelos Biológicos
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Assoc Res Otolaryngol
Asunto de la revista:
OTORRINOLARINGOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Reino Unido