tirsdag den 29. april 2014

CDK5, ME and EHS

...continued from previous post CDK5, ME and TRPA1: “Is the Cdk5 upregulation in ME responsible for other phosphorylations? What might Cdk5 further have on its conscience? To be continued…”

I found an article that might have an answer:

This study, Bioinformatic survey for new physiological substrates of Cyclin-dependent kinase 5, resulted in a very promising list of 132 putative phosphorylation sites for Cdk5, of which, 51 are specifically phosphorylated in brain tissue, and some are involved in functions regulated by Cdk5 such as axonal growth, synaptic plasticity and neurotransmission. Other phosphorylation sites in the researcher’s list suggest that Cdk5 might regulate processes through mechanisms not previously recognized such as the control of mRNA splicing.

I picked a few concrete suggestions from the list of putative sites phosphorylated by CDK-5 detected in vivo in brain samples:

  • NOS, nitric oxide synthase
  • Protein TANC1, tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 1, postsynaptic scaffold protein
  • Protein TANC2, tetratricopeptide repeat, ankyrin repeat and coiled-coil containing 2, postsynaptic scaffold protein
  • MAST1, microtubule asscociated serine/threonine protein kinase 1, postsynaptic protein that interact with beta-2-syntrophin
  • Metabotropic glutamate receptor 1

Dysregulated NOS is a hypothesis in ME.

And the proteins participate in a synaptic protein complex of: NMDAR, PSD-95, TANC1/2, nNOS, β2-syntrophin and MAST1. And glutamate is involved in the regulation of the complex.

nNOS is localized to NMDAR by the PDZ-domain adaptor protein PSD95.

Is there a CDK5 dysregulation of the nNOS – NMDAR complex in ME?

And I found a little more to the puzzle:

In the previous CKD5-blogpost I mentioned the ME-MCS connection. Another connection is the MCS-Electromagnetic Hypersensitivity (EHS) connection. Some patients have both ME, MCS and EHS. These conditions may have reduced levels of glutathione in common, references:

Metabolic and Genetic Screening of Electromagnetic Hypersensitivity Subjects as a Feasible Tool for Diagnostics
Intervention and Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology

But could CDK5 also be involved in a shared biochemistry?

Yes: p25/CDK5 is partially involved in neuronal injury induced by radiofrequency electromagnetic field exposure

The data from this study demonstrate that radiofrequency electromagnetic field (RF-EMF) exposure significantly increases CDK5 activity. Presumably RF-EMF exposure may first induce an overload in intracellular calcium, then activate calpain, and cleave p35 into p25 and p10 by calpain, and simultaneously hyperactivate CDK5 by p25.

 …and then we are in trouble, please look at the figure in the previous CDK5-blogpost.

The good news is that Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity. The study shows that GSTP1 directly inhibits CDK5 activity in vitro and also inhibits via an indirect ROS-dependent regulation. The bad news is, if ME, MCS, EHS patients also have ”glutathione problems”.

More research on this is definitely wanted!