Acidosis-related pain and its receptors as targets for chronic pain

Tissue acidosis is a pathophysiological phenomenon accompanying tissue injury, inflammation and ischemia. Environmental acidic changes have been proved to induce nociceptive activation, damage cell matrix, trigger endoplasmic reticulum stress, and even cause neuronal and glial cells death (Goldman, Pulsinelli, Clarke, Kraig, & Plum, 1989; Razaq, Wilkins, & Urban, 2003; Sharma, Kaur, Bhatnagar, & Kaur, 2015; Steen, Reeh, Anton, & Handwerker, 1992). Tissue acidosis can be observed in various clinical pain disorders. For example, rheumatoid arthritis (RA) can feature proton accumulation in the synovial fluid; the synovial fluid pH value is 7.3 in normal humans but pH 6.6 in RA patients (Goldie & Nachemson, 1969). Apart from clinical evidence, acid stimulation to the peripheral tissues triggers nociceptive responses in experiment settings. In a human study, direct intradermal acid (pH 5.2) stimulation induces mechanical hypersensitivity in the skin regions (Steen & Reeh, 1993). Additionally, animal research disclosed that activation of nociceptive C-fiber, rather than mechanosensitive Aβ and Aδ fibers, responds to pH 6.1 acidic stimulation (Steen et al., 1992). The above phenomena suggest that certain receptors in the nociceptive neurons are responsible to detect the extracellular pH changes, and their activation sequentially trigger nociceptive signaling activation. A number of proton-sensing receptors have been identified currently, including members of acid-sensing ion channels (ASICs), transient receptor potential (TRP) channels, two-pore potassium (K2P) channels, proton channels (otopetrin [OTOP]), and proton-sensing G-protein-coupled receptors (Fig. 1). Of note, the effects of acid signaling pathway on pain development are not always positive. On the contrary, mounting evidence has shown activation of acid signaling can also involve an antinociceptive function (W. N. Chen & Chen, 2014). In additional, acid signaling is also involved in pruriception (itch sensation) and proprioception (S. H. Lin et al., 2016; Lin et al., 2017; Z. Peng et al., 2015). In this review, we provide a comprehensive overview of how these proton-sensing molecules participate in acidosis signaling and pain chronification. We also investigate their pathogenic roles in the clinical painful disorders, with a particular focus on ASIC, TRP, and GPCRs.

ASICs are a group of amiloride-sensitive, proton-gated voltage-independent ion channels that belong to the epithelial sodium channel/ degenerin channel family (Baron, Voilley, Lazdunski, & Lingueglia, 2008; Waldmann, Champigny, Bassilana, Heurteaux, & Lazdunski, 1997; Wichmann & Althaus, 2020). At present, six subtypes encoded by four different ASIC functional genes in humans and rodents have been identified (S. H. Lin, Sun, & Chen, 2015), including ASIC1a (Waldmann, Champigny, et al., 1997), and ASIC1b (Bassler, Ngo-Anh, Geisler, Ruppersberg, & Grunder, 2001; C. C. Chen, England, Akopian, & Wood, 1998) encoded by Accn2 via different promoters, ASIC2a (Price, Snyder, & Welsh, 1996; Waldmann, Champigny, Voilley, Lauritzen, & Lazdunski, 1996) and ASIC2b (Lingueglia et al., 1997; Waldmann et al., 1996) encoded by Accn1 via different promoters, ASIC3 by Accn3 (Waldmann et al., 1997), and ASIC4 by Accn4 (Akopian, Chen, Ding, Cesare, & Wood, 2000; Grunder, Geissler, Bassler, & Ruppersberg, 2000). The central nervous system (CNS) primarily expresses ASIC1a, ASIC2a, and ASIC2b (Garcia-Anoveros, Derfler, Neville-Golden, Hyman, & Corey, 1997; Price et al., 1996; Waldmann et al., 1996), and ASIC3 and ASIC1b are predominantly expressed in the peripheral nervous system (PNS), at least in rodents (Alvarez de la Rosa, Zhang, Shao, White, & Canessa, 2002). With the exception of ASIC1b (Hoagland, Sherwood, Lee, Walker, & Askwith, 2010), almost all known ASIC subunits are present in the mammalian brain. ASICs are also expressed in various other tissues, such as vascular smooth muscle, skeleton, bladder, immune cells, gastrointestinal tract and its related nervous system (Grifoni, Jernigan, Hamilton, & Drummond, 2008; Mukerji, Yiangou, Agarwal, & Anand, 2006; Ni et al., 2018; Page et al., 2005; Sun et al., 2014). These ASIC subtypes can form functional homo- or heterotrimeric protein complexes, resulting in channels with distinct properties (Zha, 2013). Each ASIC subtype differs in proton sensitivity, kinetics and pharmacological responses (Hesselager, Timmermann, & Ahring, 2004). In the regard of activation property, ASIC1a and ASIC3 are especially sensitive to changes in pH, with pH sensitivity ranging from 6.2 to 6.8 and 6.2 to 6.7, respectively (Benson et al., 2002; C. C. Chen et al., 1998; Waldmann, Bassilana, et al., 1997; Waldmann, Champigny, et al., 1997). In comparison, the pH-sensitive ranges for ASIC1b and ASIC2a are 5.1 to 6.2 and 4.1 to 5.0, and ASIC4 is not activated by protons at all (Akopian et al., 2000; Grunder et al., 2000).

ASIC1a is distributed in neurons and can be detected in the CNS or PNS (S. H. Lin, Sun, & Chen, 2015; Waldmann, Champigny, et al., 1997). Actually, ASIC1a is the most populated ASIC subunit in the brain regions (J. Wu et al., 2016). In addition to its distribution in neuronal soma, ASIC1a is also found in the dendrites and axons (Price et al., 2014). Besides mediating acid-induced responses in neurons, ASIC1a also functions to modulate acidosis-induced physiological changes in the CNS (S. H. Lin, Sun, & Chen, 2015). ASIC1a participates in the control of endogenous opioid levels and its inhibition triggers an analgesic effect in rodents (Mazzuca et al., 2007). Moreover, ASIC1a also involves various functions of synaptic plasticity and neuromodulation functions other than pain, such as memory and fear behaviors (W. G. Li et al., 2016; Wang et al., 2018; Wemmie et al., 2002). ASIC1a is present in peripheral tissues, including the vasculature, intestinal tracts, and bladder (Chung et al., 2010; X. Dong et al., 2011; Kobayashi, Yoshiyama, Zakoji, Takeda, & Araki, 2009). The distribution of ASIC1a suggests its participation in the pain signaling of these visceral organs, which was further corroborated by clinical biopsy evidence (Alvarez-Berdugo et al., 2018; Han et al., 2022; Homma et al., 2013; Sanchez-Freire et al., 2011; Ustaoglu et al., 2021).

ASIC1b is the most selectively expressed subunit in peripheral sensory neurons and has a role in peripheral nociception and pain (C. C. Chen et al., 1998; Cristofori-Armstrong, Budusan, & Rash, 2021; Diochot et al., 2012). There is currently no evidence for its distribution in the CNS. ASIC1b can form heterotrimeric channels with other subtypes, such as ASIC3 or ASIC1a, and present different properties and functions.

Similar to ASIC1a, ASIC2 is expressed at high levels in the CNS (J. Wu et al., 2016). However, ASIC2 subunits alone only induce minor currents in cerebral neurons even under high acid stimuli (pH 4.0) (Askwith, Wemmie, Price, Rokhlina, & Welsh, 2004). In association with ASIC1a or ASIC3, ASIC2 can further form heterotrimers and have diverse functions (Kellenberger & Schild, 2015). For example, ASIC1a/2 is predominantly expressed in the brain cortex (Sherwood, Lee, Gormley, & Askwith, 2011), and ASIC2a is believed to facilitate ASIC1a surface trafficking in the brain(N. Jiang et al., 2017). Both ASIC2a and ASIC2b interact with ASIC1a and constitute units of different properties, pH sensitivity and permeability to ion (Askwith et al., 2004; Benson et al., 2002; Hesselager et al., 2004). Unlike ASIC2a, ASIC2b alone does not form a functional unit itself (Chu, Papasian, Wang, & Xiong, 2011). However, co-expression of ASIC2b with ASIC1a confers unique properties to heteromeric channels in the CNS neurons, such as permeability to calcium in addition to sodium ions (Sherwood et al., 2011). ASIC2 is also expressed in the dorsal root ganglia (DRG) of the PNS (B. G. Peng et al., 2004; Price et al., 2000). The colocalization of ASIC2 and mechanosensitive sensory neurons in the DRG suggests its involvement in mechanical sensation and pain modulation (Garcia-Anoveros, Samad, Zuvela-Jelaska, Woolf, & Corey, 2001; Montano et al., 2009; Staniland & McMahon, 2009).

ASIC3 is the most important ASIC subtype in the PNS and is mainly located in DRG neurons (Sluka & Gregory, 2015). In rodents, 60% of the DRG neurons express ASIC3, while 35% and 50% express ASIC1a and ASIC2b, respectively (Papalampropoulou-Tsiridou, Labrecque, Godin, De Koninck, & Wang, 2020). In humans, ASIC3 is present in up to 70% of primary sensory neurons (Papalampropoulou-Tsiridou et al., 2022). Single-cell RNAseq studies reveal ASIC3 is not only expressed in small-diameter peptidergic DRG neurons (mainly nociceptors), but also in pruriceptors and non-nociceptive low threshold mechanoreceptors, as well as proprioceptors (Tavares-Ferreira et al., 2022; Usoskin et al., 2015; Zheng et al., 2019). The ASIC3-expressed primary afferent nociceptive neurons innervate various peripheral organs, including skin, muscle, skeleton, and viscera (Y. R. Cheng, Jiang, & Chen, 2018; Montalbetti, Rooney, Marciszyn, & Carattino, 2018). Of note, ASIC3 is expressed at an exclusively higher level in the nociceptive neurons of muscle (50%) than skin (10%) (Molliver et al., 2005). Little information is available on the distribution of ASIC3 in the CNS, and its function may be associated with emotion modulation and anti-epileptic mechanism (Cao et al., 2016; W. L. Wu, Lin, Min, & Chen, 2010). The anatomic distribution of ASIC3 suggests its role in detecting tissue acidosis and pain modulation in peripheral tissues, especially in the muscular region.

ASIC4 mainly locates in the CNS (Donier, Rugiero, Jacob, & Wood, 2008; Hoshikawa et al., 2017; S. H. Lin et al., 2015). Similar to ASIC2b, ASIC4 itself does not form a functional subunit and is not activated by protons (Akopian et al., 2000). Therefore, its role in somatosensory processing and physiological activators remains to be fully studied despites its expression throughout the brain region. ASIC4 is considered to modulate the properties of other ASICs in heteromeric configurations (Donier et al., 2008). For example, by downregulating ASIC1a and ASIC3 expression, ASIC4 can modulate the acid-induced current of ASICs. Additionally, ASIC4 may also participate in emotional modulation by attenuating ASIC1a activity (S. H. Lin, Chien, et al., 2015).

TRP channels are non-selective cation channels located mostly on the plasma membrane of somatosensory neurons and numerous cell types (Julius, 2013). Most TRPs are polymodal channels and detect various environmental stimuli, such as mechanical, temperature and chemical insults (Julius, 2013). Numerous TRP subtypes respond to protons and express in nociceptors; examples are vanilloid (TRPV1 and TRPV4) (Suzuki, Mizuno, Kodaira, & Imai, 2003; Tominaga et al., 1998), ankyrin (TRPA1) (de la Roche et al., 2013), canonical (TPRC4 and TRPC5) (Semtner, Schaefer, Pinkenburg, & Plant, 2007), polycystic (TRPP2 and TRPP3)(R. B. Chang, Waters, & Liman, 2010) and melastatin (TRPM7) (Pattison, Callejo, Smith, & E., 2019). Among the TRP channels sensitive to acid stimulation, TRPV1 and TRPA1 are the most investigated polymodal nociception sensors, and both detect thermal or chemical stimuli to activate sensory neurons and produce acute or persistent pain (Julius, 2013). TRPV1 is activated by various chemical or thermal stimuli, including noxious heat (>42 °C), capsaicin, arachidonic acid, ethanol, and camphor as well as protons (Caterina et al., 1997; Mickle, Shepherd, & Mohapatra, 2015). Actually, TRPV1 is the first TRP channel shown to be directly sensitive to protons (Caterina et al., 1997; Tominaga et al., 1998). TRPV1 is widely distributed in the DRG, trigeminal ganglia, peripheral nerve terminals, skin and viscera, with sensitivity to acidic pH < 5.9 (Nilius & Owsianik, 2011; Tominaga et al., 1998).

TRPV1 and ASIC3 are commonly co-expressed in primary afferent sensory neurons. In comparison, ASIC3 is more sensitive to peripheral pH change and mediates more prominent currents than TRPV1 in the acidic environment of pH > 6.0 (Blanchard & Kellenberger, 2011). TRPA1 is considered a noxious cold sensor as well as chemo-nociceptor (Story et al., 2003). Similar to TRPV1, TRPA1 is detected in DRG and trigeminal ganglia neurons (Nilius & Owsianik, 2011). Human TRPA1 is directly activated by protons within a pH range of5.4 to 7.0 (de la Roche et al., 2013).

The family of proton-sensing GPCR includes ovarian cancer GPCR 1 (OGR1), GPCR 4 (GPR4), T-cell death-associated gene 8 (TDAG8), and G2 accumulation (G2A). These receptors were originally identified as lipid receptors: sphingosylphosphorylcholine for OGR1 and GPR4, lysophosphatidylcholine (LPC) for GPR4 and G2A, and psychosine for TDAG8 (Murakami, Yokomizo, Okuno, & Shimizu, 2004; J. Q. Wang et al., 2004; Zhu et al., 2001). Because the publications for OGR1, GPR4 and G2A have been retracted, whether they are lipid receptors remains to be elucidated.

In 2003, OGR1 and GPR4 were identified as proton-sensing receptors, and TDAG8 and G2A were later found to respond to protons as well (Table 1) (Ishii, Kihara, & Shimizu, 2005; Ludwig et al., 2003; Murakami et al., 2004; J. Q. Wang et al., 2004). OGR1 is fully activated in a pH range of 6.8 to 6.4 and induces inositol triphosphate (IP3) production and calcium signals (Ludwig et al., 2003; Mogi et al., 2005). Its activation can indirectly induce cyclic adenosine monophosphate (cAMP) accumulation via prostaglandin I2 action in human aortic smooth muscle cells (Tomura et al., 2005). OGR1 also senses shear stress in endothelial cells and membrane stretch in neuronal progenitor cells and OGR1 responsiveness to proton is stretch-dependent (Wei et al., 2018; J. Xu et al., 2018). GPR4 responds to proton then couples to the Gs protein to induce cAMP accumulation (pH 6.8–5.5) and to G12/13 protein/Rho signaling pathway (pH 7.2–6.4) and GPR4 activation also increases intracellular calcium level through calcium channels (Y. H. Huang, Su, Chang, & Sun, 2016; Ludwig et al., 2003; A. Tobo et al., 2015; M. Tobo et al., 2007; J. Q. Wang et al., 2004). TDAG8 (GPR65) was initially identified from apoptotic T cells and was found responsive to psychosine (Choi, Lee, & Choi, 1996; Im, Heise, Nguyen, O'Dowd, & Lynch, 2001). TDAG8 is fully activated by proton at pH 6.8 to 6.0, and its activation induces cAMP accumulation (Choi et al., 1996; J. Q. Wang et al., 2004).

G2A (GPR132) is so named because it induces G2 cell cycle arrest in lymphocytes (Weng et al., 1998). G2A responds to protons at pH range of 7.5 to 6.6 to induce IP3 production and IP production can be inhibited by pertussis toxin, indicating that G2A activation couples to Gi/o protein (Murakami et al., 2004). Later studies found that G2A is unable to generate significant responses to pH 7.5–6.6 stimulation and it actually activates the Gi/o pathway at low acid stimulation (pH 5.5) (Y. H. Huang et al., 2016; Radu, Nijagal, McLaughlin, Wang, & Witte, 2005). Site-direct mutagenesis studies in proton-sensing GPCRs has identified five critical proton-sensing histidine residues: His17 (N-terminal), His20 (N-terminal), His84 (first outer loop), His169 (second extracellular loop), and His269 (helix VII). OGR1 and GPR4 have all the histidine residues, and TDAG8 has two (His17 and His20). Instead of these five histidine residues, G2A has other positively charged amino acids, arginine and lysine to sense acidosis, which may explain why G2A has less sensitivity to pH (Ludwig et al., 2003; Murakami et al., 2004; Tomura, Mogi, Sato, & Okajima, 2005). Once G2A forms a heteromer with OGR1, proton sensitivity is increased in the heteromer, and the downstream signaling pathway is switched to Gi/o signaling (Y. H. Huang et al., 2016). Although the originally identified ligands LPC for G2A remains arguable, LPC treatment enhanced the cell surface expression of G2A and led to spontaneous internalization (L. Wang et al., 2005). G2A was also found as a receptor of 9-hydroxyoctadecadienoic acid (9-HODE) (Obinata, Hattori, Nakane, Tatei, & Izumi, 2005).

Besides the importance of histidine residues to sense protons, a unique triad of buried acidic residues, a Glu and a pair of Asps was recently suggested to be also essential for pH-sensing and modulator binding. TDAG8, OGR1, and GPR4 share a unique triad of buried acidic residues in tertiary structure with position at transmembrane 4 (TM4), TM2 and TM7 (Rowe, Kapolka, Taghon, Morgan, & Isom, 2021). Acidic triad mutants have decreased pH sensitivity. The conserved Asp site of the triad can be bound to Na+, a negative allosteric modulator for pH-sensing. In the presence of Na+, the sensitivity of OGR1 to pH 7 is decreased.

Two more receptors, GPR151 and GPR31, were identified as novel proton-sensing GPCRs (Mashiko, Kurosawa, Tani, Tsuji, & Takeda, 2019). Yet, these two receptors do not have conserved amino acids as classic proton sensing GPCRs. GPR151 is a galanin receptor (GALR4), but Gpr151-transfected ND7/23 cells showed no activity or responded very weakly to galanin stimulation (Holmes et al., 2017). GPR151 was later identified to respond to proton in the pH range of 6.6 to 5.6 (Mashiko et al., 2019) (Table 1). GPR31 is a receptor for 12-hydroxyeicosatetraenoic acid [12-(S)-HETE], a metabolite of arachidonic acid by 12-lipoxygenase action. GPR31 also responds to proton with a maximal activation at pH 5.8 (Mashiko et al., 2019). However, G-protein coupling and downstream signaling pathway for GPR151 and GPR31 are still unclear (Table 1).

Given that pH homeostasis is critical in cellular functions, not surprisingly, proton sensing GPCRs are expressed in various cell types and have diverse cellular functions. Studies of human tissues found that OGR1 transcript is expressed in brain, lung, and placenta; GPR4 mRNA is highly expressed in lung, less in heart and kidney, and even lower in liver, skeletal muscle and pancreas (Mahadevan et al., 1995; Y. Xu & Casey, 1996). TDAG8 mRNA is specifically expressed in thymus; G2A transcript is rich in spleen and thymus, and weak in heart and lung (Choi et al., 1996; Weng et al., 1998). Using RT-PCR technique, all four receptors were found to be expressed in diverse non-neuronal tissues, including bladder, heart, kidney, liver, lung, skeletal muscle, small intestine, spleen, stomach, testis (C. W. Huang et al., 2007). Other studies also found that OGR1 is expressed in brown adipose tissue, type 17 CD4 (Th17) cells, and neutrophils (C. W. Huang et al., 2007; H. Li et al., 2009; McAleer, Fan, Roar, Primerano, & Denvir, 2018; Murata et al., 2009); GPR4 in endothelial cells of lung, colon, heart or kidney (Sun et al., 2010; Tabula Muris et al., 2018; Wang et al., 2018); G2A in leukocytes, myeloid cells, the nervous system and lymphoid cancers (C. W. Huang et al., 2007; Uhlen et al., 2015; Uhlen et al., 2019; Uhlen et al., 2017).

The OGR1 family receptors are also found in neuronal tissues and immune cells, including cerebrum, cerebellum, brainstem, spinal cord, DRG, TG, microglia, macrophages, neutrophils, and T cells (Table 2). The role of OGR1 family in acidosis-related pain is probably given their expression pattern on nociceptors. Of total mouse DRG neurons, 26% expressed OGR1, 29% GPR4, 28% TDAG8, and 32% G2A. Approximately 82% of OGR1, 81% of GPR4, 77% of TDAG8, and 75% of G2A are co-stained with peripherin, a marker of small-diameter nociceptors, while 65% of OGR1, 63% of GPR4, 47% of TGAD8, and 48% of G2A are expressed in IB4-positive non-peptidergic neurons (C. W. Huang et al., 2007). Approximately 30%–40% of DRG neurons express at least two proton-sensing GPCRs. The high-degree of co-localization between two proton-sensing genes could reflect the presence of heteromers could be essential for their functions as the proton-sensitivity of G2A is increased after it forms a heteromer with OGR1.

These proton-sensing GPCRs are also co-localized with ASIC3 and TRPV1 (C. W. Huang et al., 2007). Of the ASIC3-positive neurons, 48% are co-expressed with OGR1, 60% with GPR4, 59% with TDAG8, and 68% with G2A. Among TRPV1-expressing neurons, 26%, 22%, 40%, and 41% are co-labeled with OGR1, GPR4, TDAG8, and G2A, respectively. The OGR1 family receptors respond to proton at the range that ASIC3 is activated, it is not surprised that they have a higher degree of co-localization with ASIC3 rather than with TRPV1. Perhaps the OGR1 family may serve as modulators of ion channels to mediate acidosis-induced pain.

GPR151 is widely expressed in the spinal cord, brain, peripheral nervous system, testis, liver, kidney and stomach (Costigan et al., 2002; Ignatov, Hermans-Borgmeyer, & Schaller, 2004; Zingoni et al., 1997). In DRG neurons, GPR151 is co-expressed with IB4 and P2X3 but less so with NF200 and CGRP (Xia et al., 2021).

K2P channels is among the potassium channels responsible for stabilizing the resting membrane potential by providing potassium leakage conductance (Benarroch, 2022). These channels also function as polymodal sensors to detect environmental stimulation, including acidosis (Alloui et al., 2006; Benarroch, 2022; Honore, 2007; Maingret, Patel, Lesage, Lazdunski, & Honore, 1999). Fifteen members of the K2P family have been identified and are divided into six subfamilies according to their structural and function (TREK, TASK, TWIK, THIK, TRESK, and TALK subfamilies) (Feliciangeli, Chatelain, Bichet, & Lesage, 2015). K2P channels are highly expressed in DRG neurons and participate in regulating neuronal excitability (Alloui et al., 2006; Plant, 2012). Among the K2P subtypes, TREK channels mainly express in medium and small C-fibers that sense noxious stimuli and are thus the most investigated targets in pain research (Acosta et al., 2014; Alloui et al., 2006; Maingret et al., 1999). TREK-1 (K2P2.1) and TREK-2 (K2P10.1) form a functional subclass of K2P channels, and have opposite responses to external acid stimulation; TREK-2 showed prominent activation by pH 6.0, while TREK-1 is inhibited by extracellular acidification (S. E. Kim, Kim, Woo, & Kim, 2020; Niemeyer, Cid, Pena-Munzenmayer, & Sepulveda, 2010; Sandoz, Douguet, Chatelain, Lazdunski, & Lesage, 2009). Additionally, TASK-1, 2, 3 are also expressed in nociceptive sensory neurons expressing TRPM8, TRPV1 or tyrosine hydroxylase and are inhibited by extracellular acidification within physiological ranges between pH 7.3 and 6.4 (Duprat et al., 1997). Pharmacological activation of TASk3-containing channels showed antinociceptive effects in mouse models of acute and chronic pain (Liao et al., 2019).

Nav is a transmembrane protein widely distributed in the membrane of excitable cells, such as neurons and rhabdomyocytes (de Lera Ruiz & Kraus, 2015). Its activity is mainly regulated by the membrane potential, and it mediates electrical signaling, including nociceptor activation (J. Wang, Ou, & Wang, 2017). Nav 1.1, Nav 1.6, Nav 1.7, Nav 1.8, and Nav 1.9 participate in sensory signaling (Bennett, Clark, Huang, Waxman, & Dib-Hajj, 2019). Among voltage-gated sodium channels, Nav 1.7 is preferentially expressed in the PNS and uniquely sensitive to acid stimulation (Smith et al., 2011). Acidosis can inhibit 42% peak conductance of mouse Nav1.7 with an IC50 of pH 5.95. Clinical research indicated that dysfunction of the channel Nav 1.7 alters nociceptive processing in human diseases; gain-of function mutation in SCN9A has been identified in patients with chronic pain syndromes (Estacion et al., 2008; Faber et al., 2012; Tanaka et al., 2017) and a loss-of-function mutation was reported in patients with congenital insensitivity to pain (Cox et al., 2006; Goldberg et al., 2007; McDermott et al., 2019). Of note, Nav 1.7 is considered to control the initiation of action potential and the release of presynaptic neurotransmitters in small-diameter DRG neurons (Alexandrou et al., 2016). Its deletion led to impaired nociceptive function and also enhanced the endogenous opioid system that contributes to congenital insensitivity to pain (Minett et al., 2015).

Otopetrins (OTOPs) are recently identified proton-sensing channels with 3 recognized subtypes (OTOP1, 2 and 3) (Saotome et al., 2019; Tu et al., 2018). OTOP1 is believed to function as an acid-detecting taste receptor (J. Zhang et al., 2019). Various receptors in addition to OTOPs have been proposed to mediate sour taste sensation, such as epithelial Na + channels and ASICs (Gilbertson, Avenet, Kinnamon, & Roper, 1992; Roper & Chaudhari, 2017; Ugawa et al., 2003). OTOP1 and OTOP3 are steeply activated when the extracellular pH is lowered below 6.0, and 5.5, respectively (Teng et al., 2022). In comparison, OTOP2 channels can be activated over a broad pH range (from 5 to 10). The physical function of OTOPs other than taste sensation, such as nociception, is seldom explored. Of note, oropharyngeal dysphagia caused by chronic pharyngitis is commonly associated with acid irritation from gastric acid reflux (Steward et al., 2004; Tanabe & Oridate, 2016). The association between the sour sensing receptors, such as OTOPs, and oropharyngeal pain remains to be further investigated.

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