Biliverdin Reductase Bridges Focal Adhesion Kinase to Src To Modulate Synaptic Signaling

Authors

Chirag Vasavda
Evan R Semenza
Jason Liew
Ruchita Kothari
Ryan S Dhindsa
Shruthi Shanmukha
Anthony Lin
Robert Tokhunts
Cristina Ricco
Adele M Snowman
Lauren Albacarys
Francesco Pastore
Cristian Ripoli
Claudio Grassi
Eugenio Barone
Michael D Kornberg
Xinzhong Dong
Bindu D Paul
Solomon H Snyder

Publication Date

5-10-2022

Journal

Science Signaling

DOI

10.1126/scisignal.abh3066

PMID

35536885

PMCID

PMC9281001

PubMedCentral® Posted Date

11-15-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Focal Adhesion Kinase 2, Focal Adhesion Protein-Tyrosine Kinases, Mice, Oxidoreductases Acting on CH-CH Group Donors, Phosphorylation, Receptors, N-Methyl-D-Aspartate, src-Family Kinases

Abstract

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity—the neuronal process of adapting to diverse and variable inputs—depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR−/−) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA-sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the N-methyl-D-aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.