EFFECT OF AGING ON MYOINOSITOL AND PHOSPHOINOSITIDE METABOLISM IN THECOCHLEAR AND VESTIBULAR SENSORY EPITHELIA OF THE RAT

Neurotransmission and transmembrane signaling ari among the cellular m echanisms 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 vestibu lar sensory epithelia (VSE), the hydrolysis of phosphatidylinositol 4, 5-bisphosphate (PtdInsP(2)) to the second messenger inositol 1,4,5-tri sphosphate (InsP(3)) is coupled to muscarinic cholinergic and P-2y pur inergic receptors and may be linked to calcium homeostasis. The presen t study compared the turnover of phosphoinositides (PtdInsPs), recepto r-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 signif icant increase in [H-3]inositol incorporation (per mass of protein) in to PtdInsPs plus InsPs in both sensory epithelia while the protein con tent remained unchanged. In contrast, no age-dependent differences wer e found when pre-labeled [H-3]PtdInsPs were 'chased' with non-radiolab eled myo-inositol indicating that the turnover of these lipids was una ffected. The cholinergic receptor agonist carbamylcholine and the P-2 purinergic receptor agonist adenosine 5'-O-(3-thiotriphosphate) stimul ated the release of [H-3]InsPs two- to six-fold in both organs. This a gonist-stimulated release of [H-3]InsPs (per mass of protein) was sign ificantly higher in aged animals. However, when the same stimulation w as expressed as per cent of control values, there was no age-dependent difference. Finally, the concentration of endogenous myo-inositol dec reased by 44% in the aged CSE and by 24% in the aged VSE. In contrast, levels of added myo-[H-3]inositol were higher in aged tissues. These results suggest that the increased labeling of PtdInsPs and InsPs in t he aged CSE and VSE is a consequence of the increased specific radioac tivity of the myo-[H-3]inositol precursor pool. The activity of the ph osphoinositide second messenger pathway thus appears unchanged. Howeve r, a decreased myo-inositol content may contribute to age-dependent pa thology in these tissues. myo-Inositol is an organic osmolyte and volu me regulator. Changes in osmotic pressure or turgor of hair cells coul d alter micromechanical coupling on the basilar membrane and vestibula r epithelium causing pathophysiological changes in sensory transductio n.