Voltage-Dependent Gating in a “Voltage Sensor-Less” Ion Channel

An unusual mechanism of ion channel regulation generates voltage-dependent gating in the absence of a canonical voltage-sensing domain

Engineering vanilloid-sensitivity into the rat TRPV2 channel.

The TRPV1 channel is a detector of noxious stimuli, including heat, acidosis, vanilloid compounds and lipids. The gating mechanisms of the related TRPV2 channel are poorly understood because selective high affinity ligands are not available, and the threshold for heat activation is extremely high (> 50 {degree sign}C). Cryo-EM structures of TRPV1 and TRPV2 reveal that they adopt similar structures, and identify a putative vanilloid binding pocket near the internal side of TRPV1. Here we use biochemical and electrophysiological approaches to investigate the resiniferatoxin (RTx) binding site in TRPV1 and to explore the functional relationships between TRPV1 and TRPV2. Collectively, our results support the interaction of vanilloids with the proposed RTx binding pocket, and demonstrate an allosteric influence of a tarantula toxin on vanilloid binding. Moreover, we show that sensitivity to RTx can be engineered into TRPV2, demonstrating that the gating and permeation properties of this channel are similar to TRPV1

Lipids: LPA activates TRPV1 - and it hurts

Lysophosphatidic acid, a lipid mediator, second messenger and intermediate in lipid biosynthesis, finds a new intracellular target in TRPV1. This nonselective cation channel is also targeted by the analgesic capsaicin, which acts to desensitize the channe

Structural and functional regulation of growth cone, filopodia and synaptic sites by TRPV1

Specialized neuronal structures namely growth cones, filopodia and spines are important entities by which neurons communicate with each other, integrate multiple signaling events, consolidate interacting structures and exchange synaptic information. Recent studies confirmed that Transient Receptor Potential Vanilloid sub type 1 (TRPV1), alternatively known as capsaicin receptor, forms a signaling complex at the plasma membrane and integrate multiple exogenous and endogenous signaling cues there. This receptor localizes in the neuronal growth cones and also in filopodial tips. In addition, TRPV1 is endogenously present in synaptic structures and located both in pre- and post-synaptic spines of cortical neurons. Being nonselective Ca2+-channel, TRPV1 regulates the morphology and the functions of these structures by various mechanisms. Our studies indicated that physical interaction with signaling and structural molecules, modulation of different cytoskeleton, synaptic scaffolding structures and vesicle recycling by Ca2+-dependent and -independent events are the key mechanisms by which TRPV1 regulates growth cone, filopodia and spines in a coordinated manner. TRPV1 not only regulates the morphology, but also regulates the functions of these entities. Thus TRPV1 is important not only for the detection of noxious stimuli and transmission of pain signaling, but also are for the neuronal communications and network formation