Structure and Function of Pannexins: Activation Mechanism
Project Number5R01GM114379-09
Former Number2R01GM114379-06
Contact PI/Project LeaderKAWATE, TOSHIMITSU
Awardee OrganizationCORNELL UNIVERSITY
Description
Abstract Text
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 protein-
coupled receptors, ligand-gated ion channels, and tumor necrosis factor receptors. However, it remains un-
clear 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 mole-
cules 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 subtype-
specific 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 recon-
stitution, 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 pro-
found 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 diseases.
Public Health Relevance Statement
PROJECT NARRATIVE
Pannexins are membrane channels widely distributed throughout the human body and play important roles
in inflammation and neurotransmission. Our research objective is to understand mechanisms of how pan-
nexins function at a molecular level, which may lead to the design of novel pharmacological agents to treat
inflammatory and neurological diseases.
No Sub Projects information available for 5R01GM114379-09
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