Structural basis of exogenous and endogenous modulation of the trpv2 ion channel Julia Ann Rocereta

Format:

Book

Thesis/Dissertation

Author/Creator:

Rocereta, Julia Ann, author.

Contributor:

University of Pennsylvania. Pharmacology., degree granting institution.

Language:

English

Subjects (All):

Pharmacology.

Biophysics.

Biochemistry.

Biology.

0419.

0786.

0487.

0306.

Local Subjects:

Pharmacology.

Biophysics.

Biochemistry.

Biology.

0419.

0786.

0487.

0306.

Genre:

Academic theses

Physical Description:

1 online resource (282 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Transient receptor potential (TRP) channels are a superfamily of homotetrameric ion channels that regulate diverse physiological processes. TRP vanilloid 2 (TRPV2) is a calcium-permeable, multimodal channel linked to neuronal development, immune system regulation, cardiovascular maintenance, and cancer metastasis. Despite these associations, the precise physiological role of TRPV2 remains poorly understood due to limitations in its pharmacological toolkit and species-dependent differences in channel activation. Many commonly used small molecules lack potency and selectivity, often modulating other TRP channels. In addition, human TRPV2 is significantly less responsive to activation than rodent orthologs, complicating interpretation and translation of experimental findings. To address these challenges, this dissertation combines cryo electron microscopy (cryoEM) and functional analyses to investigate the structural and mechanistic basis of exogenous and endogenous modulation of TRPV2. First, we examined the promiscuous pore blocker Ruthenium Red (RR) and identified its coordination within the selectivity filter of both TRPV2 and TRPV5. Structural comparisons reveal that RR maintains stable pore binding across conditions but adopts distinct poses upon the addition of activators, highlighting multiple means of pore blockade. Next, we investigated probenecid (PBC), which is currently under investigation for targeting TRPV2 in cardiovascular indications. We showed that PBC functions primarily as a potentiator of existing TRPV2 stimuli rather than a direct activator. CryoEM structures reveal a previously unidentified intracellular binding pocket where PBC destabilizes the C-terminal domain inactivating loop, suggesting a new mechanism of channel activation. Building on this finding, in vitro screening identified a novel small molecule agonist, AV2-1, that binds in the same PBC pocket and exhibits improved selectivity for TRPV2 relative to closely related TRP channels. Structural analysis demonstrates that AV2-1 is coordinated by several TRPV2-specific residues. Finally, we investigated species-dependent activation differences across TRPV2 orthologs. We determined the cryoEM structure of human TRPV2, revealing distinct structural features compared to rodent channels. Cross-mutation of a divergent motif between rat and human TRPV2 swapped activation phenotypes, providing a structural basis for species-dependent activation differences. Together, these investigations define novel mechanisms of TRPV2 modulation and establish structural frameworks necessary for improving our understanding of TRPV2 in human biology and evaluating its therapeutic potential

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Moiseenkova-Bell, Vera Y.; Marmorstein, Ronen Committee members: Trauner, Dirk; Murakami, Kenji

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247979852

Access Restriction:

Restricted for use by site license