Trends in Neurosciences
ViewpointSerine proteases and brain damage – is there a link?
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Protease-activated receptors
Thrombin is a serine protease that is generated by proteolysis of its precursor (prothrombin) at sites of vascular injury. Thrombin stimulation of platelets and limited proteolysis of fibrinogen enable clot formation and wound healing in blood vessels. Many of the actions of thrombin can be traced to PARs. To date, cDNAs encoding four PAR receptors (PAR1–4) have been identified1, 2, 3, 4, 5 and three of these genes (human PAR1, PAR2, PAR3) map to a single chromosome (5q13) in a gene cluster6;
Localization of protease receptors and inhibitors in the brain
The first thrombin receptor to be cloned, PAR1, is widely distributed in neurons and glia23, 24. PAR1 mRNA is widespread in prenatal rat brain tissue, and becomes more pronounced and confined to particular cell types in adult animals23, 24. This developmental profile differs from that of prothrombin mRNA, which is transiently reduced near birth25, raising the possibility that serine proteases and their receptors might play different roles in pre-, neo- and postnatal brain. Hybridization of PAR1
Entry of serine proteases into brain tissue
BBB breakdown associated with cerebrovascular insult reflects a largely nonselective increase in the permeability of brain capillaries and tight junctions to high-molecular-weight proteins (Box 2). Although serine protease extravasation into brain tissue during pathological situations is undocumented, the potential entry of serine proteases into the brain deserves careful consideration in the following three scenarios.
(1) Thrombin will enter interstitial fluid during penetrating head wound,
Pathological effects of serine proteases on neurons and glial cells
The molecular and cellular processes that lead to neuronal death following brain trauma and cerebrovascular insult are diverse and currently under intense investigation. Serine proteases trigger a variety of effects in neurons and glia that are often associated with brain damage (Fig. 3).
Outlook
An increasing body of literature describing the effects of serine proteases on glial and neuronal function suggests that understanding protease signaling in the brain could improve understanding of the neuropathology associated with BBB breakdown. The next few years will be pivotal in determining if serine protease extravasation, aberrant PAR activation, or cleavage of non-PAR substrates contribute to brain damage and thus are potential therapeutic targets. The many mechanisms by which serine
Acknowledgements
The author’s thank D. Cunningham, R. Dingledine, J.T. Greenamyre and S. Strickland for critical comments on the manuscript and the NIMH (MBG), NINDS (SFT) and John Merck Fund (SFT), whose generous support made this work possible.
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