pH Receptors: Peptides and Nociception

Acid-sensing ion channels (ASIC) are involved in a variety of sensory functions, including mechanoreception, nociception, and perception of acid taste, thus being considerably involved in the control of smooth musculature. It is suggested that FMRFa-related peptides can be endogenous regulators of these channels, primarily by modulating the rate of ASIC desensitization. Here we present two our findings. (I) The effect is strongly pH-dependent: The lower the pH used to activate ASIC, the greater the modulatory effect of RFa-related peptides, and (ii) in the small (nociceptive), but not in the large (mechanoceptive) primary somatosensory neurons, RFa-related peptides shift steady-state desensitization toward more acidic levels. We suggest that the pH dependence of the modulatory action of RFa-related peptides can be associated with the presence of positively charged arginine residues and their possible interactions with histidine residues in ASIC. The second effect should result in strongly increased phasic activity of nociceptors under conditions of moderate ischemia. Our results show that the RFa-related peptides are capable of changing the sensitivity of nociceptors to protons, as well as the temporal pattern of their activity. Short neuropeptides are usually the products of proteolysis of larger prohormone molecules. Interestingly, chronic pain is accompanied by a significant activation of proteases in dorsal root ganglion neurons, and RFa peptides have been found in the spinal dorsal horn of mammals. They may play a role in the modulation of the mammalian sensory inputs.