Phosphoinositide regulation of TRP channels

Abstract

Transient Receptor Potential (TRP) channels are activated by stimuli as diverse as heat, cold, noxious chemicals, mechanical forces, hormones, neurotransmitters, spices, and voltage. Besides their presumably similar general architecture, probably the only common factor regulating them is phosphoinositides. The regulation of TRP channels by phosphoinositides is complex. There are a large number of TRP channels where phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2 or PIP2] acts as a positive cofactor, similarly to many other ion channels. In several cases, however, PI(4,5)P2 inhibits TRP channel activity, sometimes even concurrently with the activating effect. This chapter will provide a comprehensive overview of the literature on regulation of TRP channels by membrane phosphoinositides.

Figure 1

Phosphoinositide metabolism

Figure 2

Activation of TRPM8 excised inside-out patches and planar lipid bilayers. A. Representative trace for recording of TRPM8 currents in large patches in Xenopus oocytes with 500 μM menthol in the patch pipette from (Rohacs et al., 2005). Left panel shows currents at −100 and +100 mV, from ramp protocol shown in the middle. Application of 30 μg/ml poly-Lysine and 50 μM diC₈ PI(4,5)P₂ are indicated with the horizontal lines. B. Similar excised inside out patch measurement from (Yudin et al., 2011), demonstrating the effect of 2 mM MgATP and LY294002. Right panel shows summary for 300 μM LY294002 that inhibits both PI4K and PI3K, and for 10 μM LY294002 that selectively inhibits PI3K. C. Representative measurement in planar lipid bilayers with purified TRPM8 from (Zakharian et al., 2009). In the upper trace first the TRPM8 protein shows no activity in the absence of menthol and PI(4,5)P₂, then diC₈ PI(4,5)P₂ is applied, then menthol, in the continuous presence of PI(4,5)P₂. In the bottom trace menthol and PI(4,5)P₂ is applied in the reverse order.

Figure 3

Inhibition of TRPM8 by reduction of PI(4,5)P₂ in intact cells, right panels in A,B and C show cartoon of the method used. A. Whole cell patch clamp measurement from (Daniels et al., 2009) showing inhibition of menthol induced RPM8 currents by the pharmacological PLC activator m-3M3FBS. B. Inhibition of TRPM8 activity by the rapamycin inducible 5-phosphatase from (Varnai et al., 2006). C. Inhibition of TRPM8 activity by depolarization-induced depletion of PI(4,5)P₂ in ciVSP expressing cells from (Yudin et al., 2011). Left panel shows a measurement with the active ciVSP, middle panel with an inactive mutant.