Cleavage of Mechanosensing Membrane Receptors

A Membrane Receptor as Mechanosensors

The mechanosensors responsible for the response to fluid shear stress are due to the same receptors that are used for ligand signalling. We showed this the first time for the fMPL receptor (FPR) on leukocytes. This receptor is a mechanosensor and mediates leukocyte pseudopod formation. Application of fluid shear stress downregulates the receptor on migrating leukocytes and thereby leads to pseudopod retraction and cessation of leukocyte spreading and migration.

Cleavage of a Mechanosensor in Leukocytes

Proteolytic cleavage of this receptor leads to reduced pseudopod retraction, as seen in hypertension and in the metabolic syndrome.

The lack of shear stress response by cleaved membrane receptors leads to spontaneous pseodopod formation in circulating leukocytes, a phenomenon that strongly influences microvascular hemodynamics.

Caveoli as Fluid Shear Stress Shelters for Mechanosensitive Receptors

Caveolae on the plasma membrane of many cell types (flask-shaped membrane structures) serve as an ideal structure to minimize the fluid shear stress acting on the membrane and its receptors. The small size of caveolae serves to preserves the ability of receptor agonists to diffuse into the the interior of the caveolae and bind to their respective receptors. Thus, as fluid shear stress shelters caveolae serve to differentiate between an agonist-mediate versus a fluid shear stress-mediated receptor activation. Shin, Kosawada et al.

Future Directions:

  • Develop a technique for proteomic-wide receptor cleavage
  • Determine the unchecked protease activity and receptor cleavage in human diseases that lead to lack of mechanotransduction and early signs of cell dysfunction before overt clinical disease symptoms.