Direct activation of transient receptor potential V1 by nickel ions

TRPV1 is a member of the transient receptor potential (TRP) family of cation channels. It is expressed in sensory neurons of the dorsal root and trigeminal ganglia as well as in a wide range of non-neuronal tissues. The channel proteins serve as polymodal receptors for various potentially harmful stimuli to prevent tissue damage by mediating unpleasant or painful sensations. Using Ca imaging and voltage-clamp recordings, we found that low millimolar doses of Ni 2+ (NiSO 4 ) are able to induce non-specific cation currents in a capsaicin-sensitive population of cultured mouse trigeminal ganglion neurons. In addition, we show that NiSO 4 elicits intracellular Ca 2+ transients and membrane currents in HEK293 and CHO cells heterologously expressing rat TRPV1. The use of voltage ramps from −100 to +100 mV revealed a strong outward rectification of these currents. Application of NiSO 4 to the cytoplasmic face of inside-out membrane patches did not induce any currents. However, delivering NiSO 4 to the extracellular face during outside-out recordings, we observed a significant increase in open probability paralleled by a decrease in channel conductance. When combined with other TRPV1 agonists, NiSO 4 produces a bimodal effect on TRPV1 activity, depending on the strength and concentration of the second stimulus. Outwardly directed currents induced by low doses of capsaicin and nearly neutral pH values (∼pH = 7.0–6.5) were augmented by low doses of NiSO 4 . In contrast, responses to stronger stimuli were reduced by NiSO 4 . Moreover, we were able to identify amino acids involved in the effect of NiSO 4 on TRPV1.