Biology subjects

Semenza, E. R.

Publications and source records attributed to Semenza, E. R..

3 recordsLinked to original sources

bioRxiv2021

D-cysteine is an endogenous regulator of neural progenitor cell dynamics in the mammalian brain

D-amino acids are increasingly recognized as important signaling molecules in the mammalian central nervous system. However, the D-stereoisomer of the amino acid with the fastest in vitro spontaneous racemization rate, cysteine, has not been examined in mammals. Using chiral high-performance liquid chromatography and an stereospecific luciferase assay, we identify endogenous D-cysteine in the mammalian brain. We identify serine racemase (SR), which generates the NMDA glutamate receptor co-agonist D-serine, as a candidate biosynthetic enzyme for D-cysteine. Levels of D-cysteine are enriched over twentyfold in the embryonic mouse brain compared to the adult. D-cysteine reduces the proliferation of cultured mouse embryonic neural progenitor cells (NPCs) by approximately 50%, effects not shared with D-serine or L-cysteine. The antiproliferative effect of D-cysteine is mediated by the transcription factors FoxO1 and FoxO3a. The selective influence of D-cysteine on NPC proliferation is reflected in overgrowth and aberrant lamination of the cerebral cortex in neonatal SR knockout mice. Finally, we perform an unbiased screen for D-cysteine-binding proteins in NPCs by immunoprecipitation with a D-cysteine-specific antibody followed by mass spectrometry. This approach identifies myristoylated alanine-rich C-kinase substrate (MARCKS) as a putative D-cysteine-binding protein. Together, these results establish endogenous mammalian D-cysteine and implicate it as a physiologic regulator of NPC homeostasis in the developing brain.

neuroscience↗

bioRxiv2020

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

Synapses are complex bridges that connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. However, they must remain dynamic in order to adapt to changing inputs. Here, we report that the enzyme biliverdin reductase (BVR) physically links together key molecules in focal adhesion signaling at the synapse. In challenging mice with a battery of neurocognitive tasks, we first discover that BVR null (BVR-/-) mice exhibit profound deficits in learning and memory. We uncover that these deficits may be explained by a loss of focal adhesion signaling that is both transcriptionally and biochemically disrupted in BVR-/- hippocampi. We learn that BVR mediates focal adhesion signaling by physically bridging the initiatory kinases FAK/Pyk2 to the effector kinase Src. Activated Src normally promotes synaptic plasticity by phosphorylating the N-methyl-D-aspartate (NMDA) receptor, but FAK/Pyk2 are unable to bind and stimulate Src without BVR. Src itself is a molecular hub upon which many signaling pathways converge in order to stimulate NMDA neurotransmission, positioning BVR at a prominent intersection of synaptic signaling.

neuroscience↗

bioRxiv2020

Cocaine receptor identified as BASP1

Cocaine is a behavioral stimulant with substantial abuse potential related to its positively rewarding actions 1,2. Cocaine inhibits the reuptake inactivation of neurotransmitters such as dopamine, serotonin, and norepinephrine at high nanomolar to low micromolar concentrations 2. There is evidence for substantially more potent influences of cocaine. For instance, Calligaro and Eldefrawi reported binding of [3H]cocaine to brain membranes with a dissociation constant of about 16 nM 3. At 10 nM concentration, cocaine elicits environmental place conditioning in planarians 4. Furthermore, 1nM cocaine enhances dopamine D2 receptor agonist-mediated signaling 5. Inhibition of amine reuptake by cocaine is substantially less potent than some of these high affinity actions. Thus, evidence for a specific, high affinity receptor for cocaine that mediates its behavioral actions has been lacking. We now report high affinity binding of cocaine to the membrane-associated brain acid soluble protein-1 (BASP1) with a Kd of 7 nM. Knocking down BASP1 in the striatum inhibits [3H]cocaine binding to striatal synaptosomes. Depletion of BASP1 in the nucleus accumbens diminishes locomotor stimulation, acquisition, and expression of locomotor sensitization to cocaine. Our findings indicate that BASP1 is a pharmacologically relevant receptor for cocaine and a putative therapeutic target for psychostimulant addiction.

pharmacology and toxicology↗