# Structure and Function of Pannexins: Activation Mechanism

> **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $117,414

## Abstract

ABSTRACT
Pannexins comprise a unique family of heptameric large-pore channels that are emerging as novel targets for
treating common, yet hard to cure diseases such as hypertension and chronic pain. Previous studies indicate
that Panx1 is activated through stimulation of structurally unrelated receptors such as G proteincoupled
receptors, ligand-gated ion channels, and tumor necrosis factor receptors. However, it remains unclear what
cellular mechanism(s) actually open and close the Panx1 channel downstream of such seemingly unrelated
stimuli. Furthermore, Panx2 and 3 are severely understudied and essentially nothing is known about the
activation mechanisms of these subtypes. The long-term goal is to elucidate the mechanisms underlying
pannexin gating, regulation, and physiological signaling pathways. The specific objectives for this proposal are
to identify the physiological pannexin activators and elucidate the subtype-specific activation mechanisms. The
central hypothesis is that both Panx1 and 2 are directly activated by naturally occurring signaling molecules in
living cells and that Panx1 specifically requires posttranslational modifications to be "primed" for its activation.
The rationale for the proposed research is that once the direct activation-stimuli and the subtypespecific
mechanisms are identified, it will enable us to fill the critical gap in the pannexin-dependent signaling pathway
by connecting the upstream cell-stimulation and the downstream ATP-permeable membrane pore formation. To
attain the overall objectives, the following three specific aims will be performed:1) Identify the direct pannexin
activators for living cells; 2) Elucidate the role of the N-terminal domain (NTD) in pannexin activation; and 3)
Uncover the subtype-specific structural features of pannexins. These research aims will be executed by using a
combination of a cell-based pannexin activity assay, electrophysiology, functional reconstitution, and cryo-EM.
The research proposed in this application is innovative because it introduces a novel concept that pannexins—
including the understudied Panx2—are directly activated by signaling molecules produced downstream of
various stimuli in living cells. It is also innovative because it will provide important insights into the structure of
the open channel and why Panx2 and 3 behave differently from Panx1. The proposed research is significant
because it will provide concrete molecular mechanisms for the missing link in the pannexin signaling function.
The proposed research is also expected to provide a strong structural foundation for subtype specific
mechanisms of pannexin channels. These results are expected to have profound positive impact not only
because they provide detailed basic mechanisms, but also because they will open a new door for
screening/designing pannexin-specific inhibitors—much-needed molecular tools that have great potentials to
serve as novel therapeutics for a variety of currently uncurable dis...

## Key facts

- **NIH application ID:** 11022696
- **Project number:** 3R01GM114379-08S1
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Toshimitsu Kawate
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $117,414
- **Award type:** 3
- **Project period:** 2015-09-01 → 2026-03-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11022696

## Citation

> US National Institutes of Health, RePORTER application 11022696, Structure and Function of Pannexins: Activation Mechanism (3R01GM114379-08S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11022696. Licensed CC0.

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