Open research questions in Ion Channels and Receptors

What the literature leaves open

• As indicated above, growing evidence suggests that VGSCs, particularly Nav1.7, Nav1.8, and Nav1.9, have signif- icant potential to manage conditions associated with ab- dominal pain. However, more carefully crafted studies are necessary to better understand exactly how these channels in?luence abdominal pain, especially in humans. Additional studies, in larger and more carefully phenotyped patient populations, are needed to expand our understanding of the exact clinical impacts that the VGSC elements and VGSC-targeted therapies described above have in IBD, and other related disorders (including their effects on in?lam- matory status and other gastrointestinal functions that have a potential impact on abdominal pain perception, in- cluding motility). There is also a need for more careful characterization of the precise physiological impact of VGSC variants. To date, no biophysical (e.g., electrophysio- logical, etc.) studies of any of the VGSCs has been under- taken in human neurons or neuronal models. This is im- portant, as there may be functional differences that stand- ard animal or other proxy cellular models are not capable of accurately replicating. We also need to harness our current knowledge about these channels to more effectively help our patients. For ex- ample, as outlined above, there are multiple polymor- phisms related to several VGS genes that we know of al- ready that have the potential to be used diagnostically. Most of them have not been formally categorized or, at the

  Harnessing Our Knowledge About Voltage-gated Sodium Channels to Better Manage Disorders of Abdominal Pain Perception in Inflammatory Bowel Disease · 2026 · DOI

• Abbreviations used in this paper: PEP, pancreatic enzyme prod- ucts; DC, digestive capacity; PERT, pancreatic enzyme replacement therapy; FE-1, fecal elastase; EPI, Exocrine Pancreatic Insufficiency; SIBO, small intestine bacterial overgrowth; H2, histamine receptor 2; MCTs, medium chain triglycerides. © 2026 by SMART- MD Publishing, Pittsburgh PA This article may not be reproduced in any form without written consent of SMART-MD Publishing LLC. ISSN 2997-2876 (online) ISSN 2997-2868 (print) DOI: Http://doi.org/10.69734/5ha1r127 Website: www.SMART-MD.org Winter 2026 Voltage-gated Sodium Channels & Abdominal Pain e210

  Harnessing Our Knowledge About Voltage-gated Sodium Channels to Better Manage Disorders of Abdominal Pain Perception in Inflammatory Bowel Disease · 2026 · DOI

• The six major conformations captured in this study provide detailed mechanistic insights into ASIC1a function, highlighting an unexpected intrinsic conformational variability of the TMD during both open and desensitized states of hASIC1a. These conformational rearrangements are mediated by proton or toxin binding to the ECD to produce function- ally distinct states, albeit suggesting linear TMD helices as a common denominator for otherwise slightly divergent open states. By com- parison, less is known about structural transitions and conformational plasticity in other members of the broader ENaC/degenerin family; how- ever, recent work suggests that there might be important differences in ENaCs28,52 and neuropeptide-activated FaNaCs (FMRFamide-activated sodium channels)53,54. Our study focuses on homotrimeric hASIC1a; it is important to consider how these findings might relate to heteromeric ASIC chan- nels, which also exist in the brain. Key elements implicated in gating, such as the conserved HG motif and T26 of pre-TM1 and the GAS motif of TM2, are present across ASIC subtypes, suggesting that similar con- formational transitions may underlie gating in heteromeric assemblies such as ASIC1a/1b or ASIC1a/2b. However, heteromeric channels exhibit distinct functional properties, including different proton sensitivities, compared to homomeric ASIC1a. We speculate that the distribution and relative occupancy of conformational states may differ from those captured in this study. Structural and functional characterization of heteromeric ASICs will be critical to determine the extent to which these conformations are conserved or diverge across physiologically relevant assemblies. Nature Structural & Molecular Biology

  Conformational plasticity of human acid-sensing ion channel 1a · 2026 · DOI

• Data availability statement Several limitations of the present study should be considered. Fifth, only a single concentra- tion of PGE2 (50 μM) was investigated; therefore, concentration- dependent effects could not be assessed.

  Prostaglandin E2 modulates contractility of mouse bladder smooth muscle cells · 2026 · DOI

• Further investigation of TRPM2 alterations in patient brain tissue, cerebrospinal fluid, and peripheral blood from individuals with AD, epilepsy, neuropathic pain, and stroke is needed to better ascertain the relevance of TRPM2 inhibition as a potential therapeutic strategy.

  Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders · 2026 · DOI

• Its newly identified activity against ORAI1 and ORAI2 could contribute to some of its immunomodulatory effects, although this possibility remains to be tested directly.

  TH1177, Clemastine, and Benzhydryl Derivatives Act as Novel Extracellular Blockers of ORAI Channels · 2026 · DOI

• , 2023), has emerged as a critical regulator of cell fate; however, its mechanistic basis and clinical relevance in renal cancer remain insufficiently explored.

  Development of a novel prognostic model based on TRPM4-Induced sodium overload–mediated cell death in kidney cancer · 2026 · DOI

• Although the role of TRPC1—a key mediator of endothelial calcium signaling—in maintaining cardiovascular homeostasis is well-established, its functional mechanisms in metabolic regulation warrant further investigation.

  Loss of endothelial TRPC1 aggravates metabolic dysfunction in obesity via disrupting adipose tissue homeostasis · 2025 · DOI

• However, the role of TRPM2 ion channels and their association with Toll-like receptors in pain management needs to be studied in more detail for the development of effective strategies to treat neuropathic pain.

  TLR4 induced TRPM2 mediated neuropathic pain · 2024 · DOI

• The epithelial Ca2+-selective channel TRPV6 has drawn interest due to its possible involvement in the development of cancer. One important messenger that controls a variety of signaling pathways related to cellular functions is Ca2+. It is commonly known that a significant portion of the hallmark processes in the course of cancer are caused by calcium signaling mechanisms, which are also deeply involved in the regulation of cell proliferation and death. Furthermore, TRPV6 is a strong target that can be used to further disturb the aberrant calcium homeostasis that is needed and seen in a lot of malignancies. It has been shown that decreasing TRPV6 activity by medication-induced inhibition or by lowering its expression is useful in four types of cancer: pancreatic, ovarian, breast, and prostate. Over the past few years, xenografted animal models and cancer cell lines have shown evidence that TRPV6 inhibits solid tumors. It is now also effective in humans. Numerous investigations have examined TRPV6′s regulatory mechanism and the medications that can be used to block its expression; the discovery of SOR-C13 has allowed for the exploration of new therapeutic targets for malignancies linked to TRPV6. TRPV6, therefore, has importance and value in clinique and can be employed as a marker for tumor identification and prognostic evaluation, as well as a target for disease treatment. Author Contributions: Y.W.: Conceptualization (equal); methodology (equal); writing—original draft (equal). X.D.: Conceptualization (equal); methodology (equal). R.Z.: Writing—review and editing (equal). H.L.: Writing—review and editing (equal). S.X.: Writing—review and editing Biology 2024, 13, 168 13 of 17 (equal). D.G.: Writing—review and editing (equal). D.W.A.: Writing—review and editing (equal). M.M.: Writing—review and editing (equal). X.-Z.C.: Supervision (equal); writing—review and editing (equal); project administration (equal). C.Z.: Supervision (equal); writing—review and editing (equal); project administration (equal). J.T.: Supervision (equal); writing—review and editing (equal); project administration (equal). All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the National Natural Science Foundation of China (82370715 to X.-Z.C., 82273970 and 32070726 to J.F.T., and 32270768 to C.F.Z.), the Innovation Group Project of Hubei Province (2023AFA026), the Wuhan Science and Technology Project (2022020801020272 to C.F.Z.), the International Science and Technology Cooperation Project of Hubei Province (2022EHB038 to C.F.Z.), and the National Key R&D Program of China (2023YFC2507900). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Acknowledgments: We are grateful to Qiuyu Cheng for instructing figure drawing. Conflicts of Interest: The authors declare no conflicts of interest.

  The TRPV6 Calcium Channel and Its Relationship with Cancer · 2024 · DOI

• Lack of evidence for significant neuronal loss in laminae I- III of the spinal dorsal horn of the rat in the chronic constriction injury model.

  Characterisation of cold-selective lamina I spinal projection neurons in the mouse · 2026 · DOI

• These channels may contribute to PAF-induced membrane excitability or VDCC- dependent contraction, although this remains to be examined.

  Orai1 Contributes to Platelet-Activating Factor (PAF)-Induced Contraction in Association with Voltage-Dependent Ca2+ Channel-Mediated Mechanisms in Guinea Pig Urinary Bladder Smooth Muscle · 2026 · DOI

• Members of the TRP family are expressed in many cancers, but the individual roles of TRP genes remain unclear.

  The Potential of TRPA1 as a Therapeutic Target in Cancer—A Study Using Bioinformatic Tools · 2024 · DOI

• The physiological significance of the distinct responses of TRPV1 and TRPA1 to two representative ROS, 1 O 2 and H 2 O 2 , warrants further investigation.

  TRPV1 and TRPA1 channels exhibit bifurcated sensing of singlet oxygen and hydrogen peroxide · 2026 · DOI

• The transient receptor potential melastatin 8 (TRPM8) ion channel is overexpressed in melanoma but its role as therapeutic target remains unexplored.

  Rewiring melanoma cell fate: TRPM8 modulators trigger apoptosis and boost NK cell cytotoxicity · 2026 · DOI

• Innocuous temperature sensation arises from the activity of primary afferent thermoreceptors, but how these neurons encode cool and warm at the population level remains unclear.

  Population encoding of cool and warm by thermoreceptors · 2026 · DOI

• Emerging evidence indicates that microglia play a pivotal role in the pathogenesis of epilepsy through complex and various mechanisms that is still not fully understood.

  Microglial Transient Receptor Potential Melastatin 2 Deficiency Accelerates Seizure Development via Increasing AMPAR‐Mediated Neuronal Excitability · 2025 · DOI

• Although the causal pathophysiological mechanisms remain unknown, numerous dietary nutrients have been shown to regulate gut mucosal immune function, being effective in influencing innate or adaptive immunity.

  Dietary targeting of TRPM8 rewires macrophage immunometabolism reducing colitis severity · 2025 · DOI

• Although many reviews focus comprehensively on capsaicin, most articles are limited to the medical field of capsaicin.

  Capsaicin from chili peppers and its analogues and their valued applications: An updated literature review · 2025 · DOI

• How the differential immune cell responses to these two pathogens relate to TRP-dependent defense against adhesion remains to be determined.

  TRPV1 Defends the Healthy Murine Cornea Against Staphylococcus aureus Adhesion Independently of Sensory Nerve Firing · 2025 · DOI

• Although vagal TRPV1 + nociceptive sensory neurons are known to mediate defenses against harmful agents, including pathogens, their function in lung antiviral defenses remains unclear.

  Vagal TRPV1 + sensory neurons protect against influenza virus infection by regulating lung myeloid cell dynamics · 2025 · DOI

• Copine-6 is expressed in peripheral somatosensory neurons, but its role in somatosensation remains unclear.

  Copine-6 is a TRPM3 escort protein controlling the sensitivity of sensory neurons to noxious heat · 2025 · DOI

• However, the neuroimmunomodulatory role of vagal-PNEC signaling in asthma remains poorly understood.

  Disruption of the Vagal TRPA1 ‐Pulmonary Neuroendocrine Cell Axis Reduces Asthma Severity · 2025 · DOI

• Future studies should focus on optimizing the clinical application of Nerelimomab (assessment of its bioavailability, pharmacokinetics, and safety) to enhance safety and mitigate the adverse effects of capsaicin exposure. Further, more applications of Nerelimomab in clinical treatment should be explored.

  Nerelimomab Alleviates Capsaicin-Induced Acute Lung Injury by Inhibiting TNF Signaling and Apoptosis · 2024 · DOI

• However, the impact of STIM1 on autophagy regulation during HCC metastasis remains unclear.

  Stromal interaction molecule 1/microtubule‐associated protein 1A/1B‐light chain 3B complex induces metastasis of hepatocellular carcinoma by promoting autophagy · 2024 · DOI

Most-cited papers in Ion Channels and Receptors

• The capsaicin receptor: a heat-activated ion channel in the pain pathway · Nature · 1997 · 7,895 citations
• Inositol trisphosphate and calcium signalling · Nature · 1993 · 5,382 citations
• TRP channels as cellular sensors · Nature · 2003 · 2,374 citations
• Identification of a cold receptor reveals a general role for TRP channels in thermosensation · Nature · 2002 · 2,354 citations
• Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid · Nature · 1993 · 2,166 citations
• Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate · Nature · 1983 · 2,020 citations
• Heat-dependent opening of TRPV1 in the presence of capsaicin · Nature Structural & Molecular Biology · 2021 · 238 citations
• Structural snapshots of TRPV1 reveal mechanism of polymodal functionality · Cell · 2021 · 234 citations
• TRPV1-Targeted Drugs in Development for Human Pain Conditions · Drugs · 2020 · 202 citations
• Nieuwe concepten voor het vormgeven van werkplekleren · Pedagogische Studiën · 2014 · 144 citations

Most recent work

• Rewiring melanoma cell fate: TRPM8 modulators trigger apoptosis and boost NK cell cytotoxicity · Cell Death and Disease · 2026
• Protectin DX resolves fracture-induced postoperative pain in mice via neuronal signaling and GPR37-activated macrophage efferocytosis · Journal of Clinical Investigation · 2026
• Potent Anthranilic Anilide-Based TRPM4 Channel Inhibitors Identified by a Structure–Activity Relationship Study · Journal of Medicinal Chemistry · 2026
• Unravelling the genetics of heat-responsive fruit traits in pepper [Capsicum annuum L.] via GWAS under subtropical climates · BMC Plant Biology · 2026
• Emerging Role of TRP Channels in Osteoarthritis Pathogenesis · Cells · 2026
• A single allosteric site merges activation, modulation and inhibition in TRPM5 · Nature Chemical Biology · 2026
• Large-scale investigation confirms TRPM3 ion channel dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome · Frontiers in Medicine · 2026
• Comparative Profiling of Capsicum frutescens and C. annuum Reveals Superior Bioactivities and Nutritional Advantages for Functional Food Applications · Food Science & Nutrition · 2026
• Development of a novel prognostic model based on TRPM4-Induced sodium overload–mediated cell death in kidney cancer · Frontiers in Cell and Developmental Biology · 2026
• Integrin activation by two independently regulated calcium-mediated pathways is required for neutrophil recruitment · Cell Communication and Signaling · 2026

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