Opening of an alternative ion permeation pathway in a nociceptor TRP channel

Role of the Outer Pore Domain in Transient Receptor Potential Vanilloid 1 Dynamic Permeability to Large Cations

“…Both NMDG permeability and YO-PRO1 uptake via TRPV1 are drastically affected by alterations within the central pore domain, such as mutagenesis, the presence of pore blockers, and cysteine-modifying reagents (10). This is in stark contrast to the TRPM3 omega current, which is completely insensitive to pharmacological blockade and chemical modification of the central pore but is affected by mutations within TM4 (30). Furthermore, the omega pore is impermeable to NMDG, and opening of this pathway does not alter TRPM3 ionic selectivity.…”

“…In addition to providing insight into the biophysical basis of this dynamic process, the fact that large cation selectivity could be finely tuned by outer pore mutations bolsters the argument (10) that large cations pass through the TRPV1 pore itself, as opposed to permeating a separate channel protein. A recent study has unmasked an alternative ion permeation pathway in the TRPM3 channel, distinct from the central ion-conducting pore (30). Opening of this second pathway gives rise to an inwardly rectifying cationic current that is believed to be analogous to the "omega current," previously described in voltage-gated potassium and sodium channels (31), and that flows through the "omega pore" delineated by TM1-TM4.…”

The G Protein–Coupled Receptor–Transient Receptor Potential Channel Axis: Molecular Insights for Targeting Disorders of Sensation and Inflammation

“…TRPM3 is also expressed on sensory neurons of DRG and TG, and trpm3 2/2 mice show deficiencies in heat sensation and development of inflammatory heat hyperalgesia (Vriens et al, 2011). Intriguingly, the cation permeation pathway in TRPM3 may function independently of the canonical central ion pore, allowing Na + influx and sensory neuronal excitation even after pharmacological inhibition of the central pore (Vriens et al, 2014). It remains to be determined if other TRP channels possess a similar secondary ion permeation pathway and how passage of both Ca 2+ and Na + may influence neuronal excitatory responses and other channels in a neuropathic pain setting.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…A novel permeation pathway was recently proposed for TRPM3 (Vriens et al, 2014). In addition to the canonical S5/S6 permeation pore, a secondary, independent permeation pathway may exist in the S1-S4 module (related to the "omega-pore" in voltageactivated ion channels).…”