CDK5

2022-04-20: Serine-Threonine Protein Kinase reference:

CDK5 (Cyclin-dependent kinase 5) #

(A) ‘cyclin’ is just their regulatory subunit.

• ΔFosB increases expression of CDK5 due to p35 upregulation, which (or p39) are subunits required for CDK5’s activation.

Plays a role in neuronal migration and neurite extension. Regulates apoptosis. Plays a role in Neuroplasticity.

• Phosphorylates Ser31 of Tyrosine Hydroxylase. Good thing.
• Cdk5 Phosphorylates Dopamine D2 Receptor and Attenuates Downstream Signaling - very comprehensive paper
  • Phosphorylates Ser321 at (i3 - the 3rd intracellular loop of - ) D2, which reduces agonist-stimulated expression of D2, and decreased G-protein coupling to it.
• Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors
• Cyclin-dependent kinase 5 governs learning and synaptic plasticity via control of NMDAR degradation
  • <- Loss of Cdk5 in the adult brain: improved performance in hippocampal behavioral learning tasks, enhanced synaptic plasticity and elevated currents through NMDARs. No change in NR2B mRNA, suggesting it’s all posttranscriptional.
  • Reduced LTP induction threshold
  • 9.0 ± 2.4-fold larger NMDA/AMPA fEPSP ratio. 1.4 ± 0.2-fold larger NMDA/AMPA EPSC ratio.
  • Hippocampal homogenates revealed a 1.33 ± 0.07-fold increase in NR2B levels, whereas NR1, and GluR1 levels were unaltered, and NR2A 0.86 ± 0.06.
    • 2.0-fold increase in synaptosomal NR2B
      • I’m pretty sure synaptosome implies not extrasynaptic. This changes the game.
    • 1.9 ± 0.2-fold increase in NR2B surface-to-total ratio in knockout slices
  • Significantly less Calpain-mediated NR2B degradation after NMDAR activation in hippocampal knockout slices: 3.6 ± 12.8% and 22.5 ± 8.2% of wild type after 30 and 60 min,
• Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior (Umfress et al. 12 May 2022)
  • Constitutive (whole-body) knockout is perinatally lethal, but conditional knockout (I guess only certain regions; pretty sure it’s only CNS) displays resilience to stress-induction, enhanced cognition, neuroprotection, ameliorated neurodegeneration:
    • Reduced anxiety-like behaviors and enhanced cocaine locomotor sensitization
    • Mice lacking p35 have dramatically altered cortical layer architecture and display hyperactivity/ADHD.
    • CDK5 Striatum knockout reulsts in impaired LP and altered motor learning