Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling

Sci Signal. 2022 May 10;15(733):eabh3066. doi: 10.1126/scisignal.abh3066. Epub 2022 May 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

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


  • Receptors, N-Methyl-D-Aspartate
  • Oxidoreductases Acting on CH-CH Group Donors
  • biliverdin reductase
  • Focal Adhesion Kinase 2
  • Focal Adhesion Protein-Tyrosine Kinases
  • src-Family Kinases