ProInflammatory Mediators, Stimulators of Sensory Neuron Excitability via the Expression of Acid-Sensing Ion Channels

Abstract

Tissue acidosis is an important feature of inflammation. It is a direct cause of pain and hyperalgesia. Protons activate sensory neurons mainly through acid-sensing ion channels (ASICs) and the subsequent membrane depolarization that leads to action potential generation. We had previously shown that ASIC transcript levels were increased in inflammatory conditions in vivo. We have now found that this increase is caused by the proinflammatory mediators NGF, serotonin, interleukin-1, and bradykinin. A mixture of these mediators increases ASIC-like current amplitude on sensory neurons as well as the number of ASIC-expressing neurons and leads to a higher sensory neuron excitability. An analysis of the promoter region of the ASIC3 encoding gene, an ASIC specifically expressed in sensory neurons and associated with chest pain that accompanies cardiac ischemia, reveals that gene transcription is controlled by NGF and serotonin.

The Extracellular Domain Determines the Kinetics of Desensitization in Acid-sensitive Ion Channel 1

“…Finally, swapping only the extracellular domains, CH5 and CH6, reproduced the desensitization rates of fish and rat ASIC1, respectively. We confirmed the importance of the extracellular domain by making CH7, which contains M1, M2, and amino and carboxyl termini from the rapid desensitizing fish ASIC1 ( D 56 s Ϫ1 ) and the ectodomain from rASIC2, which desensitizes very slowly and incompletely ( D Ͻ0.02 s Ϫ1 ) (20). CH7 exhibited a slow and incomplete desensitization rate, indistinguishable from wild-type rASIC2, confirming the crucial role of the ectodomain in determining D .…”

“…Indeed, most of the functional differences in the currents generated by the ASICs can be attributed to differences in desensitization rate, suggesting that this property may be important in conferring specificity to the response of the various ASICs in different regions of the nervous system. Numerous functions have been proposed for ASIC1 including a role in sensory transduction, specifically in nociception (pain induced by ischemia and inflammation) (7,9,15,20,21,24), and as modulators of synaptic transmission and long term plasticity (2, 28). For many of these functions, in particular nociception, proton sensitivity plays a fundamental role in the physiology of these channels.…”

“…Numerous functions have been proposed for ASIC1 including a role in sensory transduction, specifically in nociception (pain induced by ischemia and inflammation) (7,9,15,20,21,24), and as modulators of synaptic transmission and long term plasticity (2,28). For many of these functions, in particular nociception, proton sensitivity plays a fundamental role in the physiology of these channels.…”

ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation

“…Application of these inflammatory mediators to DRG neurons results in an increase in the number of neurons expressing ASIC currents, including ASIC3-like currents, and increased co-expression of ASIC3 and TRPV1. For ASIC3-like currents there is an increase in current density and an increased in the number of neurons expressing ASIC3 (Mamet et al, 2002). These changes in ASIC3 current should increase acid-induced excitation of ASIC3 neurons and increase the number of neurons responding to acid.…”

Ligand-gated Ion Channels

“…The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide FMRFamide and related substances, such as neuropeptides FF and SF, is reviewed in detail by Lingueglia et al (2006). Inflammatory conditions and particular pro-inflammatory mediators induce overexpression of ASIC-encoding genes, enhance ASIC currents (Mamet et al, 2002), and in the case of arachidonic acid directly activate the channel Deval et al, 2008). The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid (Deval et al, 2008).…”