Complex nervous systems require rapid nerve impulse transmission. Myelination by Schwann cells (SCs) in the peripheral nervous system (PNS) is essential for efficient saltatory conduction of action potentials.
At the center of the function of myelinated axons are the nodes of Ranvier. In the PNS, nodes are contacted by interdigitating microvilli that project from the end of the SCs to closely appose the nodal axolemma.
On the SC plasma membrane we and others have reported the presence of a protease activated-receptor, PAR1 which is concentrated at the level of the nodes (Shavit et al., 2008; Pompili et al., 2017). This receptor is a sensor for proteases (in particular for thrombin).
In peripheral nerves after injury a rapid rise in thrombin activity can be measured and when this protease is applied to peripheral nerve fibers it determines a conduction block (Shavit et al., 2008; Gera et al., 2016).
Other than PAR1, thrombin can also cut and activate other members of the PAR family. Thus, aim of the present project will be to assess the expression and distribution of the other PAR family members in peripheral nerves. We also aim to analyze how thrombin affects the morphology and function of SCs in sciatic nerve. Our hypothesis is that low levels of thrombin favors nerve repair acting through PAR1 while high concentrations of this protease also activates the other PARs inducing nerve damage and conduction block.
Since there are currently no therapies to effectively protect myelin, or to promote myelin regeneration after PNS injury there is a great need to identify druggable target proteins that are integral regulators governing myelin production.
As a whole, our preliminary data indicate that thrombin (in the high nanomolar range) determines a disarrangement of the nodes of Ranvier of the PNS characterized by paranodal demyelination accompanied to an enlargement of the SLI. At the same concentration in SC cultures thrombin induces a rapid peak in intracellular calcium (unpublished results). What remains to be elucidated is which receptor is responsible for this dramatic effect. Are other PARs in addition to PAR1 present on the SCs surface? Are they concentrated at the level of the nodes?
Our project is aimed to address these questions. Since in CNS PARs are key elements in governing myelin maintenance, our project has great potentials since at present, with the exception of PAR1, no data are available concerning the expression, location and function of the other members of the PAR family in peripheral nerves.
Knowing which receptor is responsible for the neurotrophic or detrimental function of thrombin on peripheral nerves will improve our understanding of the degeneration/regeneration of nerves in PNS diseases and after injury. In addition, antagonists specific for the different PARs are available and some of them are already in the clinical practice for treatment of cardiovascular events (i.e. vorapaxar).