Journal
SCIENCE
Volume 377, Issue 6606, Pages 621-629Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abm1638
Keywords
-
Categories
Funding
- National Institutes of Health [5R35CA210068]
- Richard A. and Susan F. Smith President's Innovation Award
- Sidman Family Foundation
- Michael B. Rukin Charitable Foundation
- Kenneth C. Griffin Charitable Research Fund
- George and Marie Vergottis Foundation
- Boston Investment Council
Ask authors/readers for more resources
Kynurenic acid (KynA) has tissue-protective effects in ischemia models, and this study demonstrates that activation of GPR35 and interaction with ATPIF1 may be the underlying mechanism. These findings provide a rationale for developing specific GPR35 agonists for the treatment of ischemic diseases.
Kynurenic acid (KynA) is tissue protective in cardiac, cerebral, renal, and retinal ischemia models, but the mechanism is unknown. KynA can bind to multiple receptors, including the aryl hydrocarbon receptor, the a7 nicotinic acetylcholine receptor (a7nAChR), multiple ionotropic glutamate receptors, and the orphan G protein-coupled receptor GPR35. Here, we show that GPR35 activation was necessary and sufficient for ischemic protection by KynA. When bound by KynA, GPR35 activated G(i)- and G(12/13)-coupled signaling and trafficked to the outer mitochondria membrane, where it bound, apparantly indirectly, to ATP synthase inhibitory factor subunit 1 (ATPIF1). Activated GPR35, in an ATPIF1-dependent and pertussis toxin-sensitive manner, induced ATP synthase dimerization, which prevented ATP loss upon ischemia. These findings provide a rationale for the development of specific GPR35 agonists for the treatment of ischemic diseases.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available