Activation of TRPV4 Channels (hVRL-2/mTRP12) by Phorbol Derivatives*

By Hiroyuki Watanabe, John B Davis, D. Smart, J. Jerman, Graham D. Smith, P. Hayes, J. Vriens, W. Cairns, Ullrich Wissenbach, J. Prenen and 4 more. Journal of Biological Chemistry, 2002

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We have studied activation by phorbol derivatives of TRPV4 channels, the human VRL-2, and murine TRP12 channels, which are highly homologous to the human VR-OAC, and the human and murine OTRPC4 channel. 4α-Phorbol 12,13-didecanoate (4α-PDD) induced an increase in intracellular Ca2+ concentration, [Ca2+] i , in 1321N1 cells stably transfected with human VRL-2 (hVRL-2.1321N1) or HEK-293 cells transiently transfected with murine TRP12, but not in nontransfected or mock-transfected cells. Concomitantly with the increase in [Ca2+] i , 4α-PDD activated an outwardly rectifying cation channel with an Eisenman IV permeation sequence for monovalent cations that is Ca2+-permeable withP Ca/P Na = 5.8. Phorbol 12-myristate 13-acetate also induced an increase in [Ca2+] i but was ∼50 times less effective than 4α-PDD. EC50 for Ca2+ increase and current activation was nearly identical (pEC50 ∼ 6.7). Similar effects were observed in freshly isolated mouse aorta endothelial cells which express TRP12 endogenously. By using 4α-PDD as a tool to stimulate TRP12, we showed that activation of this channel is modulated by [Ca2+] i ; an increase in [Ca2+] i inhibits the channel with an IC50 of 406 nm. Ruthenium Red at a concentration of 1 μm completely blocks inward currents at −80 mV but has a smaller effect on outward currents likely indicating a voltage dependent channel block. We concluded that the phorbol derivatives activate TRPV4 (VR-OAC, VRL-2, OTRPC4, TRP12) independently from protein kinase C, in a manner consistent with direct agonist gating of the channel.

Subfields: Complementary and alternative medicine, Pulmonary and Respiratory Medicine, Sensory Systems

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In Sensory Systems

Citations in the corpus

TRP Channels (2012, neutral): “Other potent activators of TRPV4 are synthetic phorbol esters like 4α-phorbol 12,13-didecanoate (4αPDD), 4α-phorbol 12,13-dihexanoate (4αPDH), and lumi-4αPDD, as well as GSK1016790A (193, 407, 468).”
An introduction to TRP channels. (2006, background): “55-11μM ~2 agonist (66-72) I,Ca HEK NADA TRPV1 40nM agonist (66, 95) Ca HEK OLDA TRPV1 258nM agonist (95, 96) Ca HEK OEA TRPV1 2μM 1 agonist (97) I X PDDHV TRPV1 125nM agonist (98) B,Ca CHO PDDHV TRPV4 125nM agonist (99) I, Ca ? PPAHV TRPV1 157nM,667nM agonist (70, 96, 100-102) I, Ca HEK,CHO PI(4,5)”
Trp ion channels and temperature sensation. (2006, background): “TRPV4, originally identified as an osmosensory ion channel, is also activated by warm temperatures (25◦C–34◦C) (Guler et al. 2002, Liedtke et al. 2000, Strotmann et al. 2000, Watanabe et al. 2002).”
Heat-Evoked Activation of the Ion Channel, TRPV4 (2002, background): “Regardless, these findings and the recently demonstrated activation of TRPV4 by phorbol derivatives (Watanabe et al., 2002) suggest that this protein, like TRPV1, can be regulated by an array of partially convergent physical and chemical stimuli.”