Transient receptor potential channels meet phosphoinositides - PubMed (original) (raw)

Review

Transient receptor potential channels meet phosphoinositides

Bernd Nilius et al. EMBO J. 2008.

Abstract

Transient receptor potential (TRP) cation channels are unique cellular sensors that are involved in multiple cellular functions, ranging from transduction of sensory signals to the regulation of Ca(2+) and Mg(2+) homoeostasis. Malfunctioning of TRP channels is now recognized as the cause of several hereditary and acquired human diseases. At the time of cloning of the first Drosophila TRP channel, a close connection between gating and phosphatidylinositol phosphates (PIPs) was already recognized. In this review, we summarize current knowledge about the mechanisms of interaction between TRP channels and PIPs, and discuss the possible functional implications of TRP-PIP interactions to human physiology and pathophysiology.

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Figures

Figure 1

Figure 1

PIP binding on TRP channels. (A) Known binding sites of PIPs on TRP channels are shown. The localization is indicated. (B) Putative PIP-binding site in PH-like domains in human TRP channels are shown for all TRP channels (note that no PH-like motifs were found for TRPV1 and TRPV2). From all human TRP channels, PH-like domains were identified. n and c mark the localization in the N- and C-terminus, respectively, together with the amino-acid positions. Positively charged residues are in blue. The length of each human TRP channel is indicated.

Figure 2

Figure 2

Mechanisms causing functional changes in TRP channel activity. (A) Binding of intracellular parts of the channel to PI(4,5)P2 increases the probability of the channel spent in an open configuration. (B) PI(4,5)P2 interacts with a normally inhibitory factor thereby activating the channel. (C) PI(4,5)P2 binding requires an adaptor protein, and only in this configuration, channel activity can be modulated. (D) A TRP channel associates with an agonist-delivering PLC forming a signalplex. For details, see text. Note that these mechanisms might also be able to initiate inhibition of the channel. (E) Application of PI(4,5)P2 to excised patches containing TRPM4 dramatically shifts the voltage dependence of channel activation towards more negative potentials, thereby activating the physiological membrane potentials of the channels (for details, see Nilius et al, 2006). (F) Activation of TRPM4 by elevation of the intracellular Ca2+ concentration [Ca2+]i is sensitized by the application of PI(4,5)P2 (Nilius et al, 2006).

Figure 3

Figure 3

Diseases linked to PIP metabolism. A scheme of the PIP metabolism including some critical kinases (PIxK, in red) and phosphatases (x-ppase in blue) is shown. The boxes shown refer to defective enzyme functions that can lead to human diseases. For details, see Blero et al, 2007 and Krauss and Haucke, 2007. (SHIP, P5-phosphatase; PTEN, tyrosine P5-phosphatase; MTM, myotubularins (1–7), i.e., P3-phosphatases; IpgD, invasion plasmid gene D P4 phosphatase).

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