Effect of aging on myo-inositol and phosphoinositide metabolism in the cochlear and vestibular sensory epithelia of the rat

Neurotransmission and transmembrane signaling are among the cellular mechanisms affected in the aging nervous system. In the inner ear, the phosphoinositide second messenger cascade is of particular interest as a target of the aging process. In both the cochlear (CSE) and vestibular sensory epithelia (VSE), the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP₂) to the second messenger inositol 1,4,5-trisphosphate (InsP₃) is coupled to muscarinic cholinergic and P_2y purinergic receptors and may be linked to calcium homeostasis. The present study compared the turnover of phosphoinositides (PtdlnsPs), receptor-mediated release of inositol phosphates (InsPs), and concentrations of endogenous myo-inositol in the CSE and VSE of young (3 months) and aged (24 months) Fischer-344 rats. In the aged rat, there was a significant increase in [³H]inositol incorporation (per mass of protein) into PtdlnsPs plus InsPs in both sensory epithelia while the protein content remained unchanged. In contrast, no age-dependent differences were found when pre-labeled [³H]PtdInsPs were 'chased' with non-radiolabeled myo-inositol indicating that the turnover of these lipids was unaffected. The cholinergic receptor agonist carbamylcholine and the P₂ purinergic receptor agonist adenosine 5′-O-(3-thiotriphosphate) stimulated the release of [³H]InsPs two- to six-fold in both organs. This agonist-stimulated release of [³H]InsPs (per mass of protein) was significantly higher in aged animals. However, when the same stimulation was expressed as per cent of control values, there was no age-dependent difference. Finally, the concentration of endogenous myo-inositol decreased by 44% in the aged CSE and by 24% in the aged VSE. In contrast, levels of added myo-[³H]inositol were higher in aged tissues. These results suggest that the increased labeling of PtdlnsPs and InsPs in the aged CSE and VSE is a consequence of the increased specific radioactivity of the myo-[³H]inositol precursor pool. The activity of the phosphoinositide second messenger pathway thus appears unchanged. However, a decreased myo-inositol content may contribute to age-dependent pathology in these tissues, myo-inositol is an organic osmolyte and volume regulator. Changes in osmotic pressure or turgor of hair cells could alter micromechanical coupling on the basilar membrane and vestibular epithelium causing pathophysiological changes in sensory transduction.