Joseph Santos-Sacchi

A.B. Columbia College, 1973, Ph.D Columbia University, 1978

Professor, Departments of Surgery (Otolaryngology), Cellular and Molecular Physiology, and Neurobiology; Interdepartmental Neuroscience Program, Yale University School of Medicine

Our research efforts are directed at understanding normal peripheral auditory function so that eventually inner ear deafness can be treated effectively.

The exquisite sensitivity and frequency resolving power of the mammalian inner ear depends upon interactions between the two receptor cells of the organ of Corti, inner (IHC) and outer (OHC) hair cells. Whereas inner hair cells appear to function solely as receptors of acoustic information, OHCs function both as receptors and effectors, producing motile responses as a function of transmembrane potential fluctuations. These motile responses are believed to modify the mechanical input to the inner hair cells which receive the majority of afferent innervation, thereby enhancing the gross frequency tuning afforded by basilar membrane mechanics. Currently, we are studying the effector role of the OHC with electrophysiological and displacement measurement techniques using isolated OHCs from the guinea pig. In particular, we use the whole cell voltage clamp to study the voltage dependence of the mechanical response, and the corresponding nonlinear charge associated with the motility voltage sensor. Estimates of the mechanical frequency response are made in order to assess the potential significance of OHC motility in the in vivo feedback scheme. In addition to the work on OHCs, we are also involved with studies on electrical coupling in the supporting cells, as well as characterization of the ionic currents in these cells and in spiral ganglion cells.

Selected Publications

Bai, J.-P., Navaratnam,D., Samaranayake,H., and Santos-Sacchi, J. C-terminal charge reversals alter OHC mechanical activity. Neuroscience Letters, in press, 2006.

Santos-Sacchi J. (guest Editor for special issue) Membranes and Their Interacting Partners in Peripheral Auditory Function : Foreword: Let's Hear It for the Membranes! J. Membrane Biology, May 25 (Epub ahead of print), 2006.

He DZ, Zheng J, Kalinec F, Kakehata S, Santos-Sacchi J. Tuning in to the Amazing Outer Hair Cell: Membrane Wizardry with a Twist and Shout. J. Membrane Biology ,, May 27 (Epub ahead of print), 2006.

Santos-Sacchi, J, Song, L, Zheng, J, and Nuttall, AL. Control of mammalian cochlear amplification by chloride anions. J. Neuroscience, 12;26(15):3992-8, 2006.

Santos-Sacchi, J, Rybalchenko, V, Bai, J-P, Song, L, and Navaratnam, D. On the temperature and tension dependence of the outer hair cell lateral membrane conductance GmetL, and its relation to prestin. Pflugers Archiv, 452(3):283-9, 2006.

Navarrete, E. and Santos-Sacchi J. On the affect of Prestin on the electrical breakdown of cell membranes. Biophys J. Feb 1;90(3):967-74, 2006.

Navaratnam, D, Bai, J-P, Samaranayake, H, and Santos-Sacchi, J. N-terminal mediated homo-multimerization of prestin, the outer hair cell motor protein. Biophys J. 2005 Nov;89(5):3345-52.

Santos-Sacchi, J, Song, L, Bai, J-P, and Navaratnam, D. Chloride and the OHC lateral membrane motor. Mechanics of Hearing Proceedings, Auditory Mechanisms: Processes and Models 2005 (in press)

Carlo Spirlì, Romina Fiorotto, Lei Song, Joseph Santos-Sacchi, Lajos Okolicsanyi, Sara Masier, Loretta Rocchi, Maria Pia Vairetti, Marina De Bernard, Saida Melero, Tullio Pozzan, Mario Strazzabosco. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a CFTR-independent mechanism. Gastroenterology. 2005 Jul;129(1):220-33.

Song, L., Seeger, A. and Santos-Sacchi J. On membrane motor activity and chloride flux in the outer hair cell: lessons learned from the environmental toxin tributyltin. Biophysical J. 2005, 88(3):2350-62..

Santos-Sacchi J. Animal Models for Otolaryngological Disorders: Part IV: Animal research in peripheral auditory physiology. in Handbook of Laboratory Animal Science. 2nd. Ed. Vol III Animal models. CRC Press, 2005

Santos-Sacchi J. and Wu, M. Protein and lipid reactive agents alter outer hair cell lateral membrane motor charge movement. J. Membrane Biology 2004 200:83-92,

Santos-Sacchi J. Determination of cell capacitance using the exact empirical solution of ∂Y/∂Cm and its phase angle. Biophysical J. 2004 87:714-727.

Santos-Sacchi J. New tunes from Corti’s organ: the outer hair cell boogie rules. Current Opinion in Neurobiology 2003 Aug;13(4):459-68.

Santos-Sacchi J. and Zhao, H.-B. Excitation of fluorescent dyes inactivates the outer hair cell integral membrane motor protein prestin and betrays its lateral mobility. Pflugers Archiv 2003 Aug;446(5):617-22.

Rybalchenko, V. and Santos-Sacchi, J. Cl- flux through a non-selective, stretch sensitive conductance influences the outer hair cell motor of the guinea pig. J Physiol (2003), 547.3, pp. 873–891.

Santos-Sacchi, J. Functional motor microdomains of the outer hair cell lateral membrane. Pflugers Archiv. 445, 331-336, 2002.

Santos-Sacchi J. and Navarrete, E. Voltage-dependent changes in specific membrane capacitance caused by prestin, the outer hair cell lateral membrane motor. Pflugers Archiv 444, 99-106, 2002.

Meltzer J, Santos-Sacchi J.Temperature dependence of non-linear capacitance in human embryonic kidney cells transfected with prestin, the outer hair cell motor protein. Neurosci Lett. 313, 141-4, 2001.

Santos-Sacchi, J., Shen, W., Zheng, J., Dallos, P.Effects of membrane potential and tension on prestin, the outer hair cell lateral membrane motor protein. Journal of Physiology (Rapid Report) 531.3, 661-666, 2001.

Takahashi, S. and Santos-Sacchi, J. Non-uniform mapping of stress-induced, motility-related charge movement in the outer hair cell plasma membrane. Pflugers Archiv, 441, 506-513, 2001.

Jahn, A. and Santos-Sacchi, J. (Eds.) Physiology of the ear. (textbook) 2nd Edition, Singular Press, 2001

Blasits, S., Maune, S. and Santos-Sacchi, J. Nitric oxide uncouples gap junctions of supporting Deiters cells from Corti's organ. Pflugers Archiv 440, 710-712, 2000.

Zhao, H-B and Santos-Sacchi, J. Voltage gating of gap junctions in cochlear supporting cells: evidence for nonhomotypic channels. J. Membrane Biology 175, 17-24, 2000.

Santos-Sacchi, J. Cell coupling in Corti's organ. Brain Research 32, 167-171, 2000.

Santos-Sacchi, J. The magnificent outer hair cell of Corti's organ. Otol Jpn 9, 111-115, 1999.

Zhao, H-B and Santos-Sacchi, J. Auditory collusion and a coupled couple of outer hair cells. Nature 399, 359-362, 1999.

Takahashi, S. and Santos-Sacchi, J. Distortion product analysis of outer hair cell motility - related gating charge. J. Membrane Biology 169, 199-207, 1999

Santos-Sacchi, J., Kakehata,S. , Kikuchi, T., Katori, Y. and Takasaka, T. Density of motility-related charge in the outer hair cell of the guinea pig is related to best frequency. Neuroscience Letters 256: 155-158, 1998.

Wu, M. and Santos-Sacchi, J. Effects of lipophilic ions on outer hair cell membrane capacitance and motility. J. Membrane Biol. 166(2):111-118, 1998.

Zhao, H-B and Santos-Sacchi, J. Effect of membrane tension on gap junctional conductance of supporting cells in Corti's organ. J. Gen. Physiol. 112(4):447-455, 1998.

Santos-Sacchi, J., Kakehata, S. and Takahashi, S. Effects of membrane potential on the voltage dependence of motility-related gating charge in outer hair cells of the guinea pig. J. Physiology (London) 510:225-235. 1998

Santos-Sacchi, J, Huang G - J. The effect of temperature on OHC nonlinear capacitance. Hearing Research 116: 99-106, 1998.

Santos-Sacchi, J, Huang G - J, and Wu, M. Mapping the distribution of outer hair cell voltage - dependent conductances by electrical amputation. Biophysical J. 73:1424-1429, 1997.

Ruggero, M.A. and Santos-Sacchi, J. Cochlear mechanics and biophysics., In: Handbook of Acoustics, (Ed. M.J. Croker), John Wiley & Sons., 1997.

Harris, D.M., Evans, B. and Santos-Sacchi, J.. Laser selective microablation of sensitized intracellular components within auditory receptor cells. SPIE 2396:260 - 265, 1996.

Kakehata, S. and Santos-Sacchi, J. Effects of lanthanides and salicylate on outer hair cell motility and associated gating charge. J. Neuroscience 16, 4881, 1996.

Hasson, T., Heintzelman, M.B., Santos-Sacchi, J., Corey, D.P., Mooseker, M.S. Expression in Cochlea and Retina of Myosin VIIa, the Gene Product Defective in Usher Syndrome Type 1b. Proceedings of the National Academy of Sciences (USA), 92(n21): 9815-9819, 1995.

Kakehata, S. and Santos-Sacchi, J. Membrane tension directly shifts voltage dependence of outer hair cell motility and associated gating charge. Biophysical J. 68, 2190-2197, 1995.

Huang, G.-J. and Santos-Sacchi, J. Motility voltage sensor of the outer hair cell resides within the lateral plasma membrane. Proc. Natl. Acad. Sci. USA 91, 12268-12272, 1994.

Sato, Y. and Santos-Sacchi, J. Calcium and hydrogen ion sensitivity of gap junctional conductance in the supporting cells of the organ of Corti. Hearing Research 80, 21-24, 1994.

Santos-Sacchi, J. Harmonics of outer hair cell motility. Biophysical J. 65, 2217-2227, 1993.

Huang, G.-J. and Santos-Sacchi, J. Mapping the distribution of the outer hair cell motility voltage sensor by electrical amputation. Biophysical J. 65, 2228-2236, 1993

Sites of Interest

Association for Research in Otolaryngology

Biophysical Society

Society for Neuroscience

NIH

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