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Our ability to sense heat, cold, and touch is fundamental to survival and underpins our interaction with the physical environment. The molecular basis of somatosensation was illuminated by the 2021 Nobel Prize in Physiology or Medicine awarded to David Julius and Ardem Patapoutian for their discoveries of temperature- and touch-sensing receptors. These receptors—predominantly members of the transient receptor potential (TRP) channel family and the Piezo mechanosensitive channels—have emerged as some of the most promising targets for next-generation analgesics and sensory therapeutics.
Profacgen provides comprehensive screening and analytical services targeting thermo- and mechanosensitive receptors. Leveraging our expertise in ion channel biology and advanced electrophysiology, we offer personalized screening campaigns, mechanistic characterization, and structure-based drug design support to accelerate your pain, sensory, and neurological drug discovery programs.
Figure 1. Distribution of TRP channels in the human body. (Zhang et al., 2023)
Background: The Molecular Logic of Temperature and Touch Sensation
Somatosensory receptors convert physical and chemical stimuli into electrical signals through the regulated flow of ions across cell membranes. The major receptor classes include:
TRPV1 (Transient Receptor Potential Vanilloid 1): Activated by noxious heat (>43 °C), capsaicin, and protons. TRPV1 is the primary detector of painful heat and inflammatory thermal hyperalgesia. Antagonists are under development for chronic pain and migraine.
TRPM8 (Transient Receptor Potential Melastatin 8): Activated by cold temperatures (<25 °C) and menthol. TRPM8 mediates innocuous cooling sensation and cold allodynia in neuropathic pain. Antagonists may treat cold hypersensitivity; agonists are explored for prostate cancer.
TRPA1 (Transient Receptor Potential Ankyrin 1): Activated by noxious cold, reactive electrophiles, and a broad range of irritants. TRPA1 is the primary sensor of environmental irritants and contributes to inflammatory and neuropathic pain.
Piezo1 and Piezo2: Large mechanosensitive cation channels essential for touch sensation, proprioception, and vascular mechanotransduction. Piezo2 is required for light touch and discriminative touch; Piezo1 regulates blood pressure through shear stress sensing.
Figure 2. Scheme depicting specific activators and modulators of various nociceptive transient receptor potential (TRP) channels on mammalian sensory neurons. (Mickle et al., 2016)
Dysfunction or dysregulation of these receptors is linked to a spectrum of human diseases:
Pressure-clamp for mechanosensitive channel activation
Two-Electrode Voltage Clamp (TEVC)
Expression in Xenopus oocytes for robust ion channel screening.
High expression of heterologous channels
Controlled temperature perfusion
Mechanical stimulation for Piezo channel activation
Cost-effective primary screen for large libraries
Automated Planar Patch-Clamp
Medium-throughput electrophysiology on QPatch or SyncroPatch platforms.
16- or 48-channel parallel recording
Higher throughput than manual patch-clamp
Precise temperature control and fast solution exchange
Structure-activity relationship profiling
Service Workflow
Applications
Pain drug discovery: Screen compounds against TRPV1, TRPA1, and TRPM8 for novel analgesics with reduced opioid liabilities
Migraine therapeutics: Evaluate TRP channel modulators for their ability to block CGRP release from trigeminal sensory neurons
Chronic cough: Identify compounds that desensitize airway TRPV1/TRPA1 without affecting protective cough reflex
Cardiovascular disease: Explore Piezo1 modulators for hypertension and vascular remodeling
Oncology: Evaluate TRPM8 and Piezo1 as targets for prostate cancer and tumor mechanobiology
Rare disease research: Characterize disease-associated channel variants and screen for corrector/potentiator compounds
Why Choose Profacgen?
Temperature-Controlled Assays: Unique capability to screen at defined temperatures (10–50 °C) for thermal-sensitive channels.
Mechanical Stimulation: Pressure-clamp and stretch assays for Piezo and other mechanosensitive channels.
Multiple Assay Modalities: FLIPR, manual patch-clamp, TEVC, and automated planar patch-clamp on a single platform.
Validated Cell Models: HEK293 and CHO lines stably expressing human TRP and Piezo channels with confirmed function.
Structural Biology Support: Cryo-EM services for ion channel structure determination to enable structure-based drug design.
Representative Case Studies
Case 1: Selective TRPA1 Antagonist Discovery for Inflammatory Pain
Background:
A biotech startup sought a TRPA1-selective antagonist for the treatment of inflammatory pain without the on-target adverse effects (hyperthermia) observed with TRPV1 antagonists. Their internal screening had identified weak TRPA1 hits but lacked the ion channel expertise to optimize selectivity over TRPV1 and hERG.
Our Solution:
Profacgen established a multi-assay screening cascade: FLIPR calcium influx assays for primary screening (TRPA1, TRPV1, TRPM8), followed by manual whole-cell patch-clamp for confirmatory pharmacology, and hERG electrophysiology for cardiac safety. Temperature-controlled FLIPR recordings at 37 °C ensured physiological relevance.
Final Results:
The campaign identified a novel chemotype with IC50 = 8 nM at TRPA1, >1,000-fold selectivity over TRPV1 and TRPM8, and no significant hERG inhibition (IC50 >30 μM). The lead compound reduced complete Freund's adjuvant (CFA)-induced mechanical allodyna by 75% in a rat model, with no effect on core body temperature. The program advanced to IND-enabling studies within 18 months.
Case 2: Piezo1 Inhibitor for Xerocytosis
Background:
A rare disease foundation needed to evaluate a series of putative Piezo1 inhibitors for the treatment of dehydrated hereditary stomatocytosis (xerocytosis), caused by gain-of-function mutations in Piezo1 that increase cation influx and dehydrate red blood cells.
Our Solution:
Profacgen expressed three patient-derived Piezo1 mutations (E756del, R2116H, M2225R) in HEK293 cells and established a Yoda1-stimulated calcium influx assay as the primary screen. Confirmed hits were characterized by whole-cell patch-clamp for their effect on Piezo1 mechanosensitivity and inactivation kinetics. Selectivity was assessed against Piezo2 and the related TRP channels.
Final Results:
Compound PZ-17 emerged as a selective Piezo1 inhibitor that reduced mutant Piezo1 current by 60% at 1 μM without affecting Piezo2. Importantly, PZ-17 normalized the cation flux in patient-derived erythrocytes, reducing mean corpuscular hemoglobin concentration (MCHC) by 15%—a magnitude predicted to significantly reduce hemolysis. The foundation funded the program through Phase I clinical trials.
Q: What makes thermo- and mechanosensitive receptors challenging drug targets?
A: These receptors are polymodal, integrating multiple stimuli (temperature, mechanical force, chemical ligands) through complex allosteric mechanisms. Their multi-transmembrane architecture makes structural studies difficult, and species differences in channel properties complicate translation from animal models to humans. Profacgen addresses these challenges through multiple assay modalities, human channel expression systems, and where available, structural biology support.
Q: Can you screen compounds using temperature as the activating stimulus?
A: Yes. Our FLIPR and electrophysiology platforms are equipped with temperature-controlled recording chambers capable of precisely controlled heating and cooling (10–50 °C). This enables compound evaluation under physiologically relevant thermal activation conditions rather than relying solely on chemical agonists.
Q: How do you assess selectivity across the TRP channel family?
A: Profacgen offers a TRP selectivity panel encompassing TRPV1–4, TRPM8, TRPA1, and TRPC5. Compounds are screened at a single concentration against all family members, with confirmatory IC50 determination at hits. This panel ensures that promising leads are not compromised by off-target activity at related channels.
Q: Do you support structure-based drug design for ion channels?
A: Yes. Profacgen offers cryo-EM structure determination services for ion channels, complemented by computer-aided drug design (CADD) capabilities. Resolved channel structures serve as templates for structure-based virtual screening, binding pose prediction, and rational optimization of lead compounds.
Q: What animal models can you access for in vivo validation?
A: Through our partner network, we can access rodent models of inflammatory pain (CFA, carrageenan), neuropathic pain (CCI, SNL), migraine (GTN, CGRP), and chronic cough. Transgenic and knockout models for specific TRP channels are also available for mechanistic validation studies.
References:
Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. TRP (Transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Sig Transduct Target Ther. 2023;8(1):261. doi:10.1038/s41392-023-01464-x
Mickle A, Shepherd A, Mohapatra D. Nociceptive trp channels: sensory detectors and transducers in multiple pain pathologies. Pharmaceuticals. 2016;9(4):72. doi:10.3390/ph9040072
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Figure 1. Distribution of TRP channels in the human body. (Zhang et al., 2023)
Figure 2. Scheme depicting specific activators and modulators of various nociceptive transient receptor potential (TRP) channels on mammalian sensory neurons. (Mickle et al., 2016)