Bortolozzi, Mario (2008) Calcium dynamics in inner ear health and disease. [Ph.D. thesis]
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Ca2+ acts as a fundamental signal transduction element in the inner ear, delivering information about sound acceleration and gravity through a small number of mechano-transduction channels in the hair cell stereocilia as far as to the ribbon synapse, where it drives neurotransmission. The genetic approach is proving fundamental in unravelling the molecular basis of Ca2+ function in the control of these key cellular processes. Ablation or missense mutations of the PMCA2 Ca2+-pump of stereocilia cause deafness and loss of balance. To investigate the physiological significance of these genetic defects, we studied PMCA2 Ca2+-extrusion in hair cells of utricle organotypic cultures from neonatal mice inner ear. Confocal Ca2+ imaging showed that the dissipation of stereociliary Ca2+ transients, induced by cytosolic photoliberation, was compromised by various degrees in PMCA2 knockout mice as well as in the mutant deafwaddler and Oblivion mice. Alteration of the intracellular Ca2+ concentration ( ) can trouble the finely tuned control mechanisms of signal transduction, thus resulting as a fundamental physiological parameter to be investigated in the comprehension of deafness mechanisms. By comparing our experimental fluorescence data with those derived from Monte Carlo numerical simulations, we provided a novel method to effectively deconvolve within cytoplasmic microdomains that would otherwise remain inaccessible to direct observation. Data analysis performed within this environment indicates that changes of hair cell basolateral during synaptic transmission are primarily controlled by the endogenous Ca2+ buffers at both short (< 1 micron) and long (tens of microns) distances from the presynaptic active zones. Furthermore, we provided quantitative estimates of concentration and kinetics of the endogenous Ca2+-buffers and Ca2+-ATPases in frog vestibular hair cells. We successfully applied mathematical models also in the study of channel permeability to second messengers of gap junctions, intercellular channels connecting supporting cells of the organ of Corti. In particular, it's known that defective permeation of cAMP or inositol 1,4,5-trisphosphate through gap junction channels is associated with peripheral neuropathies and deafness, respectively. Our model permits quantification of defects of metabolic coupling and can be used to investigate interdependence of intercellular diffusion and cross-talk between diverse signaling pathways.
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