PAR2, Keratinocytes, and Cathepsin S Mediate the Sensory Effects of Ciguatoxins Responsible for Ciguatera Poisoning

Calcium Increase and Substance P Release Induced by the Neurotoxin Brevetoxin-1 in Sensory Neurons: Involvement of PAR2 Activation through Both Cathepsin S and Canonical Signaling

“…Different profiles of PbTx-1-induced [Ca 2+ ] i increase in sensory neurons indicate that different subpopulations of neurons were present in our culture. The PbTx-1-induced calcium response in sensory neurons showed a three phases corresponding to the three phases observed in P-CTX-2-induced calcium response in sensory neurons [ 29 ]. Almost 54% of rat sensory neurons responded to PbTx-1 matching the proportions shown in mouse DRG neurons responding P-CTX-1B at 1 nM [ 64 ], and in rat DRG neurons responding to 10 nM of P-CTX-2 [ 29 ].…”

“…The PbTx-1-induced calcium response in sensory neurons showed a three phases corresponding to the three phases observed in P-CTX-2-induced calcium response in sensory neurons [ 29 ]. Almost 54% of rat sensory neurons responded to PbTx-1 matching the proportions shown in mouse DRG neurons responding P-CTX-1B at 1 nM [ 64 ], and in rat DRG neurons responding to 10 nM of P-CTX-2 [ 29 ]. Notably, 1 µM of PbTx-1 is a relevant concentration, given that PbTx-1 is about 500 times less potent than the P-CTX-1B and 50 times less potent than P-CTX-2 [ 21 , 65 ].…”

“…As PbTxs are unlikely to exert direct protease activity, we hypothesized that PAR2 activation is indirectly induced by proteases, especially Cat-S in a Na v -dependent manner [ 29 , 81 ]. Cat-S activates PAR2 in vitro [ 34 ] and induces in vivo itch, pain and inflammation in a PAR2-dependent manner [ 53 , 56 , 82 ].…”

“…A second study demonstrated that P-CTX-2-induced SP release and increase of intracellular calcium concentration ([Ca 2+ ] i ) in sensory neurons. Those effects are mediated by the increase of the protease cathepsin S (Cat-S) activity and the activation of the protease-activated receptor 2 (PAR2) in a Na v -dependent manner [ 29 ]. The involvement of these mediators in the pathophysiology of PbTx-induced sensory effects has never been studied.…”

“…In the skin, neuropeptides are released by free intra-epidermal nerve endings that are in close proximity to keratinocytes [ 59 ]. In previous work, we reported that P-CTX-2 is able to increase a SP release from sensory neurons but not from keratinocytes [ 29 ]. However, levels of SP released by DRG sensory neurons were inadequate to study the molecular actors.…”