The role of proteinase-activated receptor 2 (PAR2) in signaling in the dorsal root ganglion and lamina II of dorsal horn

Alier, KA; Endicott, J; Stemkowski, PL; Vergnolle, N1; Smith, PA. Department of Pharmacology and Centre for Neuroscience, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada. 1Department of Pharmacology and Therapeutics, University of Calgary, Alberta, T2N 4N1, Canada.

Proteinase-activated receptors (PARs) are a family of four G-coupled receptors (PARs1-4) that share a unique mechanism of activation (Vergnolle et al., 2003). This involves the cleavage of the N-terminal of the receptor exposing a tethered ligand which then binds and activates the receptor. These receptors can also be activated by specific synthetic peptides (Hollenberg and Compton, 2002) which bind to the activation site. Behavioral studies have recently implicated PAR2, which is expressed in primary afferent neurons, in nociception (Steinhoff et al., 2000).

The aim of our study was to investigate the cellular electrophysiological consequences of PAR2 activation in both the dorsal root ganglion (DRG) and lamina II of the dorsal horn. We used whole cell recording and the synthetic SLIGRL (10µM), which corresponds to tethered ligand of PAR2, and trypsin (potent endogenous activator of PAR2, 42µM). Trypsin and SLIGRL depolarized dissociated DRG cells by 5-10mVand the effect of trypsin outlasted that of SLIGRL. Trypsin duration was 5.20±0.93min (n=9) compared to 1.95±0.56min (n=7) with SLIGRL (P<0.05). Use of LRGILS (reverse synthetic peptide of SLGRIL) had no effect on DRG cells. The depolarization was associated with increased membrane conductance. Preliminary results from lamina II neurons in spinal cord slices indicated that PAR2 activation (using SLIGRL) increased the frequency and amplitude of spontaneous EPSC in cells with tonic discharge pattern but decreased both in all other cell types. SLIGRL also increased K+ channel conductance of some neurons.

The results suggest that PAR2-activation has a pro-nociceptive effect on DRG whereas the significance of its effect on lamina II neurons remain to be elucidated.

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