Non‐acidic activation of pain‐related Acid‐Sensing Ion Channel 3 by lipids

Abstract

Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid-Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying nonacidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C-fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid-induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling.

Conformational dynamics and role of the acidic pocket in ASIC pH-dependent gating

“…S3M). This correlation, together with the different current properties, further confirms that these nondesensitizing currents are profoundly different types of openings, and may be related to sustained ASIC currents induced by some chemical compounds and lipids (19,20).…”

Endomorphins potentiate acid‐sensing ion channel currents and enhance the lactic acid‐mediated increase in arterial blood pressure: effects amplified in hindlimb ischaemia

“…; Marra et al . ). The modulation of ASIC currents in all cases is presumed to be a direct interaction with the channels rather than through signalling events.…”

“…; Marra et al . ). Furthermore, the basic neuropeptide, dynorphin, can also exert potentiating effects on the ASIC1 isoform (Sherwood & Askwith, ).…”

Proton‐independent activation of acid‐sensing ion channel 3 by an alkaloid, lindoldhamine, from Laurus nobilis

“…LIN therefore represents the first ASIC3 positive modulator that displays a pronounced species specificity. In contrast to other ASIC activators (GMQ and LPC) (Alijevic and Kellenberger, ; Marra et al ., ), LIN did not shift the pH‐activation curve, implying that LIN potentiation is not a result of increased channel affinity to protons in the presence of LIN (Figure 6С). In our experiments, hASIC3‐mediated currents were completely desensitized at pH 7.3.…”