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Jaime García-Añoveros, PhDAssistant Professor
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Mechanotransduction, the process whereby a cell transforms a mechanical force into an electrochemical signal, underlies the senses of hearing, proprioception and touch. Hair cells of the inner ear detect sounds and accelerations and allow us to hear and maintain balance; some of the somatosensory neurons of the dorsal root and trigeminal ganglia detect deformations to the body and result in the perceptions of proprioception, touch and pain.
A genetic dissection of touch in the nematode Caenorhabditis elegans led to the identification of the proteins that mediate this sense in worms, which include structural components of the extracellular matrix and of the cytoskeleton, and membrane proteins called degenerins. I have demonstrated that degenerins form ion channels, and based on genetic analyses, have proposed a model whereby they connect to the cytoskeleton and extracellular matrix to become mechanically gated.
We have also found homologous proteins in mammals that form a novel family of neuronal sodium channels that are not gated by voltage but instead may be opened by extracellular acidity (BNaC or ASIC). Several BNaC isoforms are widely expressed in brain neurons, where some are localized at postsynaptic sites. An interesting hypothesis in that these channels are gated by protons released from acidic presynaptic vesicles. However, two BNaC isoforms (BNaC1a and DRASIC) are co-expressed and form heteromultimeric channels in touch-sensitive neurons (the large diameter neurons of the dorsal root and trigeminal ganglia), are transported peripherally, and localize at their specialized mechanosensory endings. Mice with a knock out of BNaC1 or DRASIC have impaired touch sensitivity. This evidence suggests that – like their homologs in nematode touch neurons – the BNaC1a and DRASIC channel proteins are subunits of the macromolecular structures that mediate innocuous touch sensation in mammals. By searching for molecular interactors, we have begun to identify additional components of the touch-transducing complex.
A related question is what are the channels that mediate painful touch. Recently, we identified a novel mouse ion channel that is exclusively expressed in nociceptor neurons (thus it is a potential target for the search of novel analgesics with minimal or no side effects). This channel protein has an ortholog in nematodes. We will knock out and test the function of this channel gene in mice, which are well suited for behavioral and physiological assays of pain, as well as in C. elegans, where genetic screens may lead to the identification of novel genes in the pain pathway.
Nagata, K., Zheng, L., Madathany, T., Castiglioni, A. J., Bartles, J. R., and García-Añoveros, J. (2007). The varitint-waddler (Va) deafness mutation in TRPML3 generates constitutive, inward rectifying currents and causes cell degeneration. Proc. Natl. Acad. Sci. USA. 105, 353-358 (E-pub ahead of print on Dec 27, 2007).
Duggan, A., Madathany, T., De Castro, S. C. P., Gerrelli, D., Guddati, K., and García-Añoveros, J. (2008). Transient expression of the conserved zinc finger gene INSM1 in progenitors and nascent neurons throughout embryonic and adult neurogenesis. J. Comp. Neurol. 507, 1497-1520.
Nagata, K., Duggan, A., Kumar, G., and García-Añoveros, J. (2005) Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J. Neurosci. 25 (16), 4052-4061. (Cover article).
Sage, C., Huang, M., Karimi, K., Gutierrez, G., Vollrath, M. A., Zhang, D.-S., García-Añoveros, J., Hinds, P. W., Corwin, J. T., Corey, D. P, and Chen, Z.-Y. (2005). Proliferation of functional hair cells in vivo in the absence of retinoblastoma protein. Science 307, 1114-8. (Epub 13 January, 2005).
*Corey, D. P., *García-Añoveros, J., *Holt, J. R., *Kwan, K Y., *Lin, S.-Y., *Vollrath, M. A., Amalfitano, A., Cheung, E. M.-L., Derfler, B. H., Duggan, A., Géléoc, G. S. G., Gray, P., Hoffman, M. P., Rehm, H. L., Tamasauskas, D., and Zhang, D.-S. (2004). TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells. Nature 432(7018):723-30. *Equal contribution.
Duggan, A., García-Añoveros, J. and Corey, D. P. (2002). The PDZ domain protein PICK1 and the sodium channel BNaC1 interact and localize at mechanosensory terminals of dorsal root ganglion neurons and dendrites of central neurons. J. Biol. Chem. 277, 5203-5208.
Garcia-Anoveros J, Samad TA, Zuvela-Jelaska L, Woolf CJ, Corey DP. Transport and localization of the DEG/ENaC ion channel BNaC1a to peripheral mechanosensory terminals of DRG neurons. J. Neurosci. 21 (8), 2678-2686.
Duggan, A., García-Añoveros, J., and Corey, D. P. (2000). Insect mechanoreception: What a long, strange TRP it’s been. Current Biology 10, R384-387.
García-Añoveros, J., García, J. A., Liu, J., and Corey, D. P. (1998) The nematode degenerin UNC-105 forms ion channels that are activated by degeneration- or hypercontraction causing mutations. Neuron 20, 1231-1241.
García-Añoveros, J., and Corey, D. P. (1997). The molecules of mechanosensation. Annu. Rev. Neurosci. 20, 567-594.
García-Añoveros, J., Derfler, B., Neville-Golden, J., Hyman, B. T., and Corey, D. P. (1997). BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proc. Natl. Acad. Sci. USA 94, 1459-1464.
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View Publications by Jaime García-Añoveros listed in the National Library of Medicine (PubMed). |
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