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Activation and regulation of TRP channels

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2008, Doctor of Philosophy, Ohio State University, Biophysics.

Mammalian TRP superfamily is composed of 28 members. Based on the sequence homology and functional similarity, they are grouped into 6 subfamilies: canonical TRP (TRPC), vanilloid TRP (TRPV), melastatin TRP (TRPM), ankyrin TRP (TRPA), polycystin TRP (TRPP), and mucolipin TRP (TRPML). TRP channels display rather diverse tissue expression pattern and physiological functions.

We mainly focused on three TRP channels: TRPV3 from TRPV subfamily; TRPC4 and TRPC5 from TRPC subfamily. For TRPV3, we performed three functional studies: first, we found that arachidonic acid (AA), together with other poly-unsaturated fatty acids (PUFAs), greatly potentiated TRPV3 channel function independent of its downstream metabolites or signaling pathways. Second, besides being potentiated by AA and other PUFAs, TRPV3 also displays an intrinsic unique functional property: sensitization upon prolonged or repetitive chemical or physical stimulations. We studied the molecular mechanism underlying this unique feature and found that calcium plays a critical role from both intracellular and extracellular sides. Third, a spontaneously occurring point mutation linked to rodent hair-less phenotype was mapped to Gly573 of TRPV3. We carried out detailed functional studies with G573C and G573S mutants of TRPV3, and discovered that these two point mutations cause constitutive channel activation and severe host cell death, which provides an important clue for the hairless phenotype.

Moreover, we studied the activation mechanism of TRPC4 and TRPC5. Strikingly, we found that in addition to the previously identified Gq/11 signaling pathway, another commonly considered inhibitory G protein-coupled receptor, Gi/o signaling pathway, was excitatory for the activation of TRPC4 and TRPC5. In fact, compared to Gq/11, the Gi/o pathway was even stronger for the activator of TRPC4/C5. We also demonstrated the synergistic effect between these two pathways. The full activation of TRPC4/C5 appeared to require both signaling pathways, indicating that TRPC4 and TRPC5 work as coincident detectors for the two important G protein signaling pathways. We further confirmed the requirement of phospholipase C (PLC) and intracellular Ca2+ for the excitatory effect of Gi/o. More detailed studies will help us understand the precise underlying mechanism of Gi/o-induced TRPC4/C5 activation.

Michael Zhu, PhD (Advisor)
Anthony Brown, PhD (Committee Member)
John Enyeart, PhD (Committee Member)
Chen Gu, PhD (Committee Member)
242 p.

Recommended Citations

Citations

  • Xiao, R. (2008). Activation and regulation of TRP channels [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1220620917

    APA Style (7th edition)

  • Xiao, Rui. Activation and regulation of TRP channels. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1220620917.

    MLA Style (8th edition)

  • Xiao, Rui. "Activation and regulation of TRP channels." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1220620917

    Chicago Manual of Style (17th edition)