Modulation of sensory neuron mechanotransduction by PKC- and nerve growth factor-dependent pathways

Abstract

Many sensations of pain are evoked by mechanical stimuli, and in inflammatory conditions, sensitivity to such stimuli is commonly increased. Here we used cultured sensory neurons as a model of the peripheral terminal to investigate the effects of inflammatory signaling pathways on mechanosensitive ion channels. Activation of two of these pathways enhanced transduction in a major population of nociceptors. The proinflammatory neurotrophin nerve growth factor caused an up-regulation of mechanically activated currents via a transcriptional mechanism. Activators of PKC, given in vitro and in vivo, also caused an increase in mechanically activated membrane current and behavioral sensitization to mechanical stimulation, respectively. The effect of activating PKC was inhibited by tetanus toxin, suggesting that insertion of new channels into the cell membrane is involved in sensitization. These results reveal previously undescribed mechanisms by which PKC and nerve growth factor synergistically enhance the response of nociceptors to mechanical stimuli, suggesting possible targets for pain treatment.allodynia ͉ dorsal root ganglia ͉ hyperalgesia ͉ mechanosensation ͉ pain

Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons

“…This potentiation is much greater than the enhancement of RA-MA currents shown previously following the treatment of primary afferent neurons with inflammatory mediators or protein kinase C activators (12,13). Previous studies have shown that functions of Piezo2 chan- , n ϭ 8).…”

“…An arrow indicates the time when the solutions are injected into the hind paws. Data represent mean Ϯ S.E., *, p Ͻ 0.05; **, p Ͻ 0.01. nels can be up-regulated through intracellular signaling pathways, including protein kinase A, protein kinase C, and EPAC1 (12,13,15), raising the possibility that osmotic swelling-induced sensitization of RA-MA channels in our study may also be mediated by these intracellular signaling pathways. Osmotic swelling may activate TRPV4 channels (28) to increase intracellular Ca 2ϩ concentrations, which may subsequently activate intracellular second messenger systems to up-regulate RA-MA channel functions.…”

“…Activators of PKC, given in vitro and in vivo, also cause increases in RA-MA currents and behavioral sensitization to mechanical stimulation, respectively (12). In a heterologous expression system, Piezo2 current amplitude is shown to be increased by bradykinin receptor ␤2 activation, and the up-reg-ulation of Piezo2 function is shown to be mediated by protein kinase A and protein kinase C (13).…”

“…In primary afferent neurons, studies have shown that RA-MA currents are up-regulated by a transcriptional mechanism by the proinflammatory neurotrophin nerve growth factor (12). Activators of PKC, given in vitro and in vivo, also cause increases in RA-MA currents and behavioral sensitization to mechanical stimulation, respectively (12).…”

Fat location defines sensation

“…Although the expression of channels in sensory neurons that contribute to mechanosensation has been shown to be up-regulated both transcriptionally and in terms of membrane trafficking by inflammatory mediators, the development of allodynia has often been associated with events in the dorsal horn (14). Intriguingly, many peptide mediators associated with small-diameter sensory neurons [calcitonin gene-related peptide (CGRP), substance P, brain-derived neurotrophic factor (BDNF)] have been shown to evoke allodynia when applied intrathecally (15)(16)(17).…”