PMC

TRP channels act as thermosensors in sensory nerves. Transient receptor cation channels expressed in sensory neurons are activated by ambient changes. TRPA1 is activated by noxious cold from 17°C and colder temperatures. TRPM8, TRPV4, and TRPV3 are activated by warmer temperatures, with a similar threshold of 25°C for TRPM8 (which senses chilling) and TRPV4. TRPV3 is activatedy by hotter temperature (33°C threshold) creating a sensory link with TRPV1 and TRPV2, which are activated by noxious heat with respective thresholds of 42°C and 52°C. All channels can also be activated by a wide variety of agonists present in the environment. Natural stimulants are indicated on the side of each channel with their most common natural source. TRP = transient receptor potential; TRPA1 = transient receptor potential cation channel, subfamily A, member 1.

Calcium flux is associated with TRPV1 and TRPA1 activation in the cell. TRPV1 and TRPA1 produce a depolarizing inward current, mainly calcium, when opened by the binding of their respective agonists, such as capsaicin (V1), acrolein (A1), resiniferatoxin (V1), or H⁺ protons (V1). GPCR agonists, such as PGE₂ or bradykinin, can also activate TRPV1 and TRPA1 channels via hydrolysis of phosphatidylinositol 4,5-bisphosphate and by production of diacylglycerol by the associated PLC. The inositol 1,4,5-triphosphate produced in parallel will release calcium from intracellular stores by binding to the inositol IP3R located on the endoplasmic reticulum membrane. In addition, as TRP channels activate, the resulting inward current depolarizes the membrane, triggering the opening of low-threshold voltage-gated sodium channels, which will further depolarize the membrane triggering the opening of voltage-gated calcium channels (VGCC). Calcium influx through VGCC and the RyR will induce elevation of intracellular calcium ([Ca²⁺]_i). This significant [Ca²⁺]_i elevation could be another mechanism regulating the activity of TRP channels, thereby inhibiting TRPV1 and activating TRPA1.^, This cycled regulation of [Ca²⁺]_i by the membrane potential (Vm) and of Vm by [Ca²⁺]_i is modulated by the capacity of the cell to clamp intracellular level of calcium, mainly via SERCA and PMCA. Ca = voltage-gated calcium channel; DAG = diacylglycerol; GPCR = G protein-coupled receptor; IP3R =1,4,5-triphosphate receptor; Na = voltage-gated sodium channels; PGE2 = prostaglandin E₂; PLC = phospholipase C; PMCA = plasma membrane calcium ATPase; RyR = ryanodine receptor; SERCA = endoplasmic reticulum Ca²⁺-ATPase. See legend for expansion of other abbreviations.