TY - JOUR
T1 - Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling
AU - Vasavda, Chirag
AU - Semenza, Evan R.
AU - Liew, Jason
AU - Kothari, Ruchita
AU - Dhindsa, Ryan S.
AU - Shanmukha, Shruthi
AU - Lin, Anthony
AU - Tokhunts, Robert
AU - Ricco, Cristina
AU - Snowman, Adele M.
AU - Albacarys, Lauren
AU - Pastore, Francesco
AU - Ripoli, Cristian
AU - Grassi, Claudio
AU - Barone, Eugenio
AU - Kornberg, Michael D.
AU - Dong, Xinzhong
AU - Paul, Bindu D.
AU - Snyder, Solomon H.
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
PY - 2022/5/10
Y1 - 2022/5/10
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.abh3066
DO - 10.1126/scisignal.abh3066
M3 - Article
C2 - 35536885
AN - SCOPUS:85130002114
SN - 1945-0877
VL - 15
JO - Science signaling
JF - Science signaling
IS - 733
M1 - eabh3066
ER -