Colloquium 15: Role of the Protease-Activated Receptors in Neural Development, Degeneration and Trauma

Signalling through protease activated receptors (PARs) is important during neural development and reappears during certain CNS disorders resulting in loss of neurons. These heptohelical G‐protein coupled receptors (GPCRs) are activated by specific proteolysis of N‐terminal fragments. How they are regulated at transcriptional and post‐transcriptional levels is of paramount importance in developing neuroprotective strategies. We and others showed in vitro that serine protease signalled apoptosis involves activation of PAR‐1 and a pathway involving coupled Gs, intracellular calcium elevation, activation of caspases, and apoptotic cell death. In vivo, after spinal cord injury in rats and during motor neuron degeneration in wobbler mice, PAR‐1 is up‐regulated in the regions most affected even prior to the onset of phenotypic motor loss in the homozygous recessive wobbler mouse. Information is beginning to appear on transcriptional regulation of PAR expression and involves several transcription factors (TFs) such as AP‐1, SP‐1, NFκB and, more recently, JAK/STAT. The regulation of PARs in the nervous system will be reviewed with an emphasis on those PARs unregulated during neurodegeneration and in response to CNS injury. In summary, immunohistochemistry, quantitative mRNA, gene array analyses of the receptor sequences present and their modulation by exogenous factors indicate that they are potential targets for therapeutic intervention to help preserve neuronal health. Acknowledgements: Supported by the Dept. of Veterans Affairs, Christopher Reeve Paralysis Foundation, ALS Association, Lied Endowment, KUMCRI and Midwest Biomedical Research Foundation.