Vanilloid Receptors

Capsaicin is a common ingredient of Indian, Indonesian and Mexican food. Tucked innocuously away inside prettily coloured peppers it explodes within the mouth like a volcano, creating a severe burning sensation (some people actually like it!). Attempts to douse the fire with water only succeed in spreading it further around the mouth and the initial pain is often followed by an outbreak of sweating. I imagine most people are familiar with this unfortunate scenario. The capsaicin content differs between different varieties

FIGURE 24.1 PUTATIVE MEMBRANE TOPOLOGY OF THE P2X RECEPTOR

Putative membrane topology of the P2X receptor, based on hydropathy analysis. By analogy with ENaC channels it seems possible that a pore loop is present, but as this is still only an hypothesis it has been indicated by a dashed line. Residues that are believed to line the channel pore are indicated.

FIGURE 24.1 PUTATIVE MEMBRANE TOPOLOGY OF THE P2X RECEPTOR

Putative membrane topology of the P2X receptor, based on hydropathy analysis. By analogy with ENaC channels it seems possible that a pore loop is present, but as this is still only an hypothesis it has been indicated by a dashed line. Residues that are believed to line the channel pore are indicated.

of pepper. In 1912, Wilbur Scoville calibrated the potency of the spice by measuring how much an extract of the pepper must be diluted until it was only barely detectable when placed on the tongue. On the Scoville scale, the relatively mild bell pepper has <1 heat units, the hotter jalapeno has 103, the fiery habanero has 105 and pure capsaicin has a massive 107 heat units.

The target with which capsaicin interacts turns out to be a ligand-gated ion channel and it was cloned by Caterina and colleagues from sensory neurones (1997). Because the vanilloid moiety is an essential component of capsaicin, they named their channel the vanilloid receptor (VR1). It is 838 amino acids long and has a predicted molecular mass of 95 kDa. Hydropathy analysis suggests that VR1 has six putative transmembrane domains (TMs), a pore loop between TMs 5 and 6, and intracellular amino and carboxy termini (Fig. 24.2). The N terminus contains a proline-rich region followed by three ankyrin repeats. The latter are domains which bind the structural protein ankyrin and are presumably involved in localising and anchoring VR1 at the nerve terminal. The vanilloid receptor shows greatest sequence homology with a family of channels that are believed to be activated by depletion of intracellular calcium stores (Montel and Rubin, 1989; Hardie and Minke, 1993). These channels are known as trp channels because the first member to be isolated caused a mutant phenotype in Drosophila known as the transient receptor potential (trp). Unlike trp channels, however, VR1 does

Vr1 Nerves

FIGURE 24.2

Putative membrane topology of VR1 based on hydropathy analysis.

FIGURE 24.2

Putative membrane topology of VR1 based on hydropathy analysis.

not appear to be gated by store depletion. VR1 is expressed almost exclusively, and at high density, in trigeminal and dorsal root sensory ganglia. This matches the distribution of nociceptive (pain-sensitive) neurones and is consistent with a role for the receptor in pain sensation.

Expression studies have demonstrated that VR1 is a non-selective cation channel with a high calcium permeability (PCa/PNa = ~10). Thus receptor activation not only causes neuronal excitation but also elevates intracellular calcium. This may explain why capsaicin acts as an excitotoxin and why continuous exposure to capsaicin for several hours kills nociceptive neurones in vivo and cells expressing VR1 in vitro (Fig. 24.3). People who regularly

Control VR1 (1:50) VR1

FIGURE 24.3 CAPSAICIN INDUCES THE DEATH OF CELLS EXPRESSING VR1

Percentage of dead cells observed 7 hr after addition of 3 uM capsaicin (black bars) or control solution (white bars) to control cells or cells expressing the vanilloid receptor VR1. From Caterina et al. (1997).

Control VR1 (1:50) VR1

FIGURE 24.3 CAPSAICIN INDUCES THE DEATH OF CELLS EXPRESSING VR1

Percentage of dead cells observed 7 hr after addition of 3 uM capsaicin (black bars) or control solution (white bars) to control cells or cells expressing the vanilloid receptor VR1. From Caterina et al. (1997).

consume very spicy food become desensitized to the effects of capsaicin, as well as other noxious stimuli. The selective destruction of nociceptive neurons may be one reason for this desensitization. Alternatively, VR1 receptors might be downregulated in some way in response to prolonged capsaicin exposure. Whatever the reason, the desensitization of pain fibres by capsaicin is the basis for the use of the spice as an analgesic in arthritis and in viral and diabetic neuropathies (it is applied topically, as a cream).

VR1 is activated both by pure vanilloids, such as capsaicin, and by pepper extracts. The relative potency of the pepper extracts in gating VR1 correlates well with their perceived hotness on the Scoville scale (Fig. 24.4, see color plate). The steepness of the dose-response curve suggests that the binding of more than one capsaicin molecule is required for receptor activation. One possible explanation for this cooperativity is that the channel is multimeric, like other channels which have a six TM topology: by analogy with the KV and CNG channels we may speculate that it is a tetramer (see Chapters 6 and 11). In addition to capsaicin, VR1 is activated by resiniferatoxin. This toxin is isolated from the spurge Euphorbia resinifera and is responsible for the powerful burning sensation and skin irritation induced by the milky sap of these plants. Ruthenium red and the synthetic antagonist capsazepine block capsaicin-induced responses. The location of the binding site for capsaicin is unknown, but because the spice is lipophilic, and therefore membrane permeant, it could act from either the outside or the inside of the membrane, or even within it. The lipophilicity of capsaicin is well known to anyone who has tried to quench the burning sensation it produces with water—all that happens is that the fire is spread around the mouth.

VR1 is not only activated by capsaicin. It also is gated by heat, which may in fact serve as the physiological stimulus. In HEK cells transfected with VR1, a rapid increase in temperature induces a large inward current, with properties resembling those of capsaicin-activated currents. A similar current is also induced in sensory neurones by noxious levels of heat (Cesare and McNaughton, 1996). The ability of high temperatures to activate VR1 may explain why capsaicin is perceived as hot. Whether an endogenous ligand for VR1 also exists is an interesting question.

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