Transient Receptor Potential Polycystin Research Articles

Inhibition of TRPP3 by calmodulin through Ca2+/calmodulin-dependent protein kinase II.

Transient receptor potential (TRP) polycystin-3 (TRPP3) is a non-selective cation channel activated by Ca2+ and protons and is involved in regulating ciliary Ca2+ concentration, hedgehog signaling and sour tasting. The TRPP3 channel function and regulation are still not well understood. Here we investigated regulation of TRPP3 by calmodulin (CaM) by means of electrophysiology and Xenopus oocytes as an expression model. We found that TRPP3 channel function is enhanced by calmidazolium, a CaM antagonist, and inhibited by CaM through binding of the CaM N-lobe to a TRPP3 C-terminal domain not overlapped with the EF-hand. We further revealed that the TRPP3/CaM interaction promotes phosphorylation of TRPP3 at threonine 591 by Ca2+/CaM-dependent protein kinase II, which mediates the inhibition of TRPP3 by CaM.

Transient receptor potential channel-dependent myogenic responsiveness in small-sized resistance arteries.

It is well documented that the inherent ability of small arteries and arterioles to regulate intraluminal diameter in response to alterations in intravascular pressure determines peripheral vascular resistance and blood flow (termed myogenic response or pressure-induced vasoconstriction/dilation). This autoregulatory property of resistance arteries is primarily originated from mechanosensitive vascular smooth muscle cells (VSMCs). There are diverse biological apparatuses in the plasma membrane of VSMCs that sense mechanical stimuli and generate intracellular signals for the contractility of VSMCs. Although the roles of transient receptor potential (TRP) channels in pressure-induced vasoconstriction are not fully understood to date, TRP channels that are directly activated by mechanical stimuli (e.g., stretch of VSMCs) or indirectly evoked by intracellular molecules (e.g., inositol trisphosphate) provide the major sources of Ca2+ (e.g., Ca2+ influx or release from the sarcoplasmic reticulum) and in turn, evoke vascular reactivity. This review sought to summarize mounting evidence over several decades that the activation of TRP canonical, TRP melastatin, TRP vanilloid, and TRP polycystin channels contributes to myogenic vasoconstriction.

TRPPing up bronchiectasis.

TRPPing up bronchiectasis.

The role of calmodulin in regulating calcium-permeable PKD2L1 channel activity.

Polycystic kidney disease 2-like-1 (PKD2L1), polycystin-L or transient receptor potential polycystin 3 (TRPP3) is a TRP superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. Although the calmodulin (CaM) inhibitor, calmidazolium, is an activator of the PKD2L1 channel, the activating mechanism remains unclear. The purpose of this study is to clarify whether CaM takes part in the regulation of the PKD2L1 channel, and if so, how. With patch clamp techniques, we observed the current amplitudes of PKD2L1 significantly reduced when coexpressed with CaM and CaMΔN. This result suggests that the N-lobe of CaM carries a more crucial role in regulating PKD2L1 and guides us into our next question on the different functions of two lobes of CaM. We also identified the predicted CaM binding site, and generated deletion and truncation mutants. The mutants showed significant reduction in currents losing PKD2L1 current-voltage curve, suggesting that the C-terminal region from 590 to 600 is crucial for maintaining the functionality of the PKD2L1 channel. With PKD2L1608Stop mutant showing increased current amplitudes, we further examined the functional importance of EF-hand domain. Along with co-expression of CaM, ΔEF-hand mutant also showed significant changes in current amplitudes and potentiation time. Our findings suggest that there is a constitutive inhibition of EF-hand and binding of CaM C-lobe on the channel in low calcium concentration. At higher calcium concentration, calcium ions occupy the N-lobe as well as the EF-hand domain, allowing the two to compete to bind to the channel.

Transient Receptor Potential Ion Channel-Dependent Toxicity of Silica Nanoparticles and Poly(amido amine) Dendrimers.

Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biologic fate and potential toxic effects. Transient receptor potential (TRP) ion channels are a large superfamily of cation channels with varied physiologic functions. This superfamily is classified into six related subfamilies: TRP canonical, TRP vanilloid (TRPV), TRP melastatin (TRPM), TRP ankyrin (TRPA), TRP polycystin, and TRP mucolipin. TRPA1, TRPM2, and TRPM8 are nonselective Ca2+-permeable cation channels which regulate calcium pathways under oxidative stress, whereas TRPV4 can be activated by oxidative, osmotic, and thermal stress as well as different fatty acid metabolites. Using a series of well characterized silica nanoparticles with variations in size (approximately 50-350 nm in diameter) and porosity, as well as cationic and anionic poly(amido amine) (PAMAM) dendrimers of similar size, we examined the toxicity of these nanoparticles to human embryonic kidney-293 cells overexpressing different TRP channels. The data show that the toxicity of mesoporous silica nanoparticles was influenced by expression of the TRPA1 and TRPM2 channels, whereas the toxicity of smaller nonporous silica nanoparticles was only affected by TRPM8. Additionally, TRPA1 and TRPM2 played a role in the cytotoxicity of cationic dendrimers, but not anionic dendrimers. TRPV4 did not seem to play a significant role in silica nanoparticle or PAMAM toxicity.

The role of transient receptor potential polycystin channels in bone diseases.

Transient receptor potential (TRP) channels are cation channels which act as molecular sensors that enable cells to detect and respond to a plethora of mechanical and environmental cues. TRPs are involved in various physiological processes, such as mechanosensation, non-inception and thermosensation, while mutations in genes encoding them can lead to pathological conditions, called "channelopathies". The subfamily of transient receptor potential polycystins (TRPPs), Polycystin 1 (PC1, TRPP1) and Polycystin 2 (PC2, TRPP2), act as mechanoreceptors, sensing external mechanical forces, including strain, stretch and fluid shear stress, triggering a cascade of signaling pathways involved in osteoblastogenesis and ultimately bone formation. Both in vitro studies and research on animal models have already identified their implications in bone homeostasis. However, uncertainty veiling the role of polycystins (PCs) in bone disease urges studies to elucidate further their role in this field. Mutations in TRPPs have been related to autosomal polycystic kidney disease (ADKPD) and research groups try to identify their role beyond their well-established contribution in kidney disease. Such an elucidation would be beneficial for identifying signaling pathways where polycystins are involved in bone diseases related to exertion of mechanical forces such as osteoporosis, osteopenia and craniosynostosis. A better understanding of the implications of TRPPs in bone diseases would possibly lay the cornerstone for effective therapeutic schemes.

A Gain-of-Function TRPP2 Ion Channel Created by Mutating Single Amino Acid in the S5 Transmembrane Domain

Mutations in polycystin-1 and TRPP2 (transient receptor potential polycystin 2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as cation channel when it is homomeric assembled, and when it forms a complex with polycystin-1. Studies on the function and regulation of TRPP2 are significantly delayed due to the lack of knowledge on its activation mechanism. Here, by applying a mutagenesis scan on the S4-S5 linker and the S5 transmembrane domain, we generated the constitutively active gain-of-function (GOF) mutant TRPP2_F604P and studied functional properties of this GOF channel.

Regulation of TRPP3 Channel Function by N-terminal Domain Palmitoylation and Phosphorylation

Transient receptor potential polycystin-3 (TRPP3) is a cation channel activated by calcium and proton and is involved in hedgehog signaling, intestinal development, and sour tasting. How TRPP3 channel function is regulated remains poorly understood. By N-terminal truncation mutations, electrophysiology, and Xenopus oocyte expression, we first identified fragment Asp-21–Ser-42 to be functionally important. We then found that deletion mutant Δ1–36 (TRPP3 missing fragment Met-1–Arg-36) has a similar function as wild-type TRPP3, whereas Δ1–38 is functionally dead, suggesting the importance of Val-37 or Cys-38. Further studies found that Cys-38, but not Val-37, is functionally critical. Cys-38 is a predicted site of palmitoylation, and indeed TRPP3 channel activity was inhibited by palmitoylation inhibitor 2-bromopalmitate and rescued by palmitoylation substrate palmitic acid. The TRPP3 N terminus (TRPP3NT, Met-1–Leu-95) localized along the plasma membrane of HEK293 cells but stayed in the cytoplasm with 2-bromopalmitate treatment or C38A mutation, indicating that TRPP3NT anchors to the surface membrane through palmitoylation at Cys-38. By acyl-biotin exchange assays, we showed that TRPP3, but not mutant C38A, is indeed palmitoylated. When putative phosphorylation sites near Cys-38 were mutated to Asp or Glu to mimic phosphorylation, only T39D and T39E reduced TRPP3 function. Furthermore, TRPP3NT displayed double bands in which the upper band was abolished by λ phosphatase treatment or T39A mutation. However, palmitoylation at Cys-38 and phosphorylation at Thr-39 independently regulated TRPP3 channel function, in contrast to previous reports about correlated palmitoylation with a proximate phosphorylation. Palmitoylation at Cys-38 represents a novel mechanism of functional regulation for TRPP3.

Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant

Mutations in polycystin-1 and transient receptor potential polycystin 2 (TRPP2) account for almost all clinically identified cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common human genetic diseases. TRPP2 functions as a cation channel in its homomeric complex and in the TRPP2/polycystin-1 receptor/ion channel complex. The activation mechanism of TRPP2 is unknown, which significantly limits the study of its function and regulation. Here, we generated a constitutively active gain-of-function (GOF) mutant of TRPP2 by applying a mutagenesis scan on the S4-S5 linker and the S5 transmembrane domain, and studied functional properties of the GOF TRPP2 channel. We found that extracellular divalent ions, including Ca(2+), inhibit the permeation of monovalent ions by directly blocking the TRPP2 channel pore. We also found that D643, a negatively charged amino acid in the pore, is crucial for channel permeability. By introducing single-point ADPKD pathogenic mutations into the GOF TRPP2, we showed that different mutations could have completely different effects on channel activity. The in vivo function of the GOF TRPP2 was investigated in zebrafish embryos. The results indicate that, compared with wild type (WT), GOF TRPP2 more efficiently rescued morphological abnormalities, including curly tail and cyst formation in the pronephric kidney, caused by down-regulation of endogenous TRPP2 expression. Thus, we established a GOF TRPP2 channel that can serve as a powerful tool for studying the function and regulation of TRPP2. The GOF channel may also have potential application for developing new therapeutic strategies for ADPKD.

Acid-induced off-response of PKD2L1 channel in Xenopus oocytes and its regulation by Ca(2.).

Polycystic kidney disease (PKD) protein 2 Like 1 (PKD2L1), also called transient receptor potential polycystin-3 (TRPP3), regulates Ca2+-dependent hedgehog signalling in primary cilia, intestinal development and sour tasting but with an unclear mechanism. PKD2L1 is a Ca2+-permeable cation channel that is activated by extracellular Ca2+ (on-response) in Xenopus oocytes. PKD2L1 co-expressed with PKD protein 1 Like 3 (PKD1L3) exhibits extracellular acid-induced activation (off-response, i.e., activation following acid removal) but whether PKD1L3 participates in acid sensing remains unclear. Here we used the two-microelectrode voltage-clamp, site directed mutagenesis, Western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence, and showed that PKD2L1 expressed in oocytes exhibits sustained off-response currents in the absence of PKD1L3. PKD1L3 co-expression augmented the PKD2L1 plasma membrane localization but did not alter the observed properties of the off-response. PKD2L1 off-response was inhibited by an increase in intracellular Ca2+. We also identified two intra-membrane residues aspartic acid 349 (D349) and glutamic acid 356 (E356) in the third transmembrane domain that are critical for PKD2L1 channel function. Our study suggests that PKD2L1 may itself sense acids and defines off-response properties in the absence of PKD1L3.

The N-Terminal Cleavage of PKD1L3 and its Effect on the Function of PKD1L3/TRPP3 Receptor/Ion Channel Complex

Transient Receptor Potential Polycystin (TRPP) channels are a family of protein that forms functional receptor/ion channel complexes with Polycystic Kidney Disease (PKD) proteins that are involved in various physiological processes. For example, PKD1/TRPP2 complex have been known to be involved in renal physiology where a mutation in either of these proteins leads Autosomal Dominant Polycystic Kidney Disease (ADPKD). Another example is PKD1L3/TRPP3 complex, a sour taste receptor candidate, which response to low pH. PKD proteins share homology with adhesion G-protein coupled receptor proteins (aGPCRs). One of the key characteristics of these proteins is that they go through autoproteolysis at N-terminal GPCR proteolystic site (GPS), before the first transmembrane segment. The cleavage yield two fragments, one N terminus fragment (NTF) and another C terminus fragment (CTF). This autoproteolysis has been extensively studied in PKD1, however due to the lack of a method to activate PKD1/TRPP2 complex, the effect of the cleavage on the function of the channel is unknown. Since PKD1L3/TRPP3 can be activated with acid, it is a good model to study the effect of the cleavage on the channel function of this complex. Here, we show that cleavage happens on PKD1L3 at the GPS site as it is in PKD1, generating NTF and CTF. Mutations at the GPS site abolish cleavage. The non-cleavable mutant lost the ability to form functional channel with TRPP3, highlighting the significance of the cleavage in the overall function of the channel complex. Interestingly, co-expressed NTF and CTF not only associate with each other, but also form a functional channel in the presence of TRPP3 in Xenopus oocytes. Furthermore, we found natively non-cleavable PKD1L3 exits as a splicing variant, indicating potential function of the non-cleaved protein.

Transient receptor potential channels as targets for phytochemicals.

To date, 28 mammalian transient receptor potential (TRP) channels have been cloned and characterized. They are grouped into six subfamilies on the basis of their amino acid sequence homology: TRP Ankyrin (TRPA), TRP Canonical (TRPC), TRP Melastatin (TRPM), TRP Mucolipin (TRPML), TRP Polycystin (TRPP), and TRP Vanilloid (TRPV). Most of the TRP channels are nonselective cation channels expressed on the cell membrane and exhibit variable permeability ratios for Ca2+ versus Na+. They mediate sensory functions (such as vision, nociception, taste transduction, temperature sensation, and pheromone signaling) and homeostatic functions (such as divalent cation flux, hormone release, and osmoregulation). Significant progress has been made in our understanding of the specific roles of these TRP channels and their activation mechanisms. In this Review, the emphasis will be on the activation of TRP channels by phytochemicals that are claimed to exert health benefits. Recent findings complement the anecdotal evidence that some of these phytochemicals have specific receptors and the activation of which is responsible for the physiological effects. Now, the targets for these phytochemicals are being unveiled; a specific hypothesis can be proposed and tested experimentally to infer a scientific validity of the claims of the health benefits. The broader and pressing issues that have to be addressed are related to the quantities of the active ingredients in a given preparation, their bioavailability, metabolism, adverse effects, excretion, and systemic versus local effects.

Gating modulation by heat of the polycystin transient receptor potential channel PKD2L1 (TRPP3)

Polycystic kidney disease 2-like 1 (PKD2L1), previously called transient receptor potential polycystin 3 (TRPP3), forms a voltage-dependent nonselective cation channel that exhibits large tail currents triggered by repolarization after depolarization. Since it has previously been proposed that temperature sensitivity of some TRP channels is linked to the voltage-dependent gating, we here investigated heating effects on PKD2L1 currents in human embryonic kidney HEK293T cells overexpressing mouse PKD2L1. Tail PKD2L1 currents were increased by heating to 32°C, but decreased at more than 36°C. Voltage dependency of the PKD2L1 channel was shifted by heating in a bimodal fashion: an increase in temperature to 32°C and to 36°C shifted the activation curves toward the left and the right, respectively. In addition, heating accelerated deactivation of tail PKD2L1 currents. To analyze the channel gating kinetics, single-channel events of the PKD2L1 channel were recorded at hyperpolarized potentials under whole-cell configurations. A rise in temperature decreased the open probability of the channel. Dwell-time analysis showed that both open and closed dwell times during heating were shorter than those at room temperature. Interestingly, a rapid temperature drop after heating markedly enhanced the PKD2L1 currents at both single-channel and whole-cell levels. The rebound activation of the PKD2L1 channel was due to an increase in the open probability but not in the single-channel conductance. These results suggest that heating opens but subsequently inactivates PKD2L1 channels, which is essential for the rebound activation of the channel after heating.

Smooth muscle cell transient receptor potential polycystin (TRPP)2 channels contribute to the myogenic response in cerebral arteries

Intravascular pressure‐induced vasoconstriction is a smooth muscle cell (myocyte)‐specific mechanism that controls systemic blood pressure and regional organ blood flow. Myocyte polycystin (TRPP)‐1 and ‐2 proteins modulate the myogenic response in mesenteric arteries, but involvement in other vascular beds is unclear. Here, we examined myocyte TRPP2 expression, cellular distribution, cation currents (ICat), and contribution to the myogenic response in cerebral arteries. Real‐time RT‐PCR amplified transcripts for TRPP1 and TRPP2, with TRPP2 being the predominant message in isolated rat cerebral artery myocytes. Western blot analysis indicated that TRPP2 protein was present in rat and human cerebral arteries. Arterial surface biotinylation and immunofluorescence indicated that TRPP2 is located primarily within the myocyte plasma membrane. Cell swelling induced by hyposmotic bath solution stimulated ICat in myocytes that were inhibited by RNAi‐mediated selective TRPP2 channel knockdown. TRPP2 knockdown did not alter myogenic tone at 20 mmHg but reduced myogenic tone at pressures between 40 and 100 mmHg. In contrast, TRPP2 knockdown did not alter membrane depolarization‐induced (60 mmol/L K+) vasoconstriction. These data indicate that TRPP2 contributes to stretch‐activated ICat in myocytes of resistance‐size cerebral arteries, leading to vasoconstriction. NIH/NHLBI.

Polycystin-2 Expression and Function in Adult Mouse Lacrimal Acinar Cells

Lacrimal glands regulate the production and secretion of tear fluid. Dysfunction of lacrimal gland acinar cells can ultimately result in ocular surface disorders, such as dry eye disease. Ca(2+) homeostasis is tightly regulated in the cellular environment, and secretion from the acinar cells of the lacrimal gland is regulated by both cholinergic and adrenergic stimuli, which both result in changes in the cytosolic Ca(2+) concentration. We have previously described the detailed intracellular distribution of inositol-1,4,5-trisphosphate receptors (IP(3)Rs), and ryanodine receptors (RyRs) in lacrimal acinar cells, however, little is known regarding the expression and distribution of the third major class of intracellular Ca(2+) release channels, transient receptor potential polycystin family (TRPP) channels. Studies were performed in adult lacrimal gland tissue of Swiss-Webster mice. Expression, localization, and intracellular distribution of TRPP Ca(2+) channels were investigated using immunocytochemistry, immunohistochemistry, and electron microscopy. The biophysical properties of single polycystin-2 channels were investigated using a planar lipid bilayer electrophysiology system. All channel-forming isoforms of TRPP channels (polycystin-2, polycystin-L, and polycystin-2L2) were expressed in adult mouse lacrimal gland. Subcellular analysis of immunogold labeling revealed strongest polycystin-2 expression on the membranes of the endoplasmic reticulum, Golgi, and nucleus. Biophysical properties of lacrimal gland polycystin-2 channels were similar to those described for other tissues. The expression of TRPP channels in lacrimal acinar cells suggests a functional role of the proteins in the regulation of lacrimal fluid secretion under physiological and disease conditions, and provides the basis for future studies focusing on physiology and pharmacology.

Bimodal effect of alkalization on the polycystin transient receptor potential channel, PKD2L1

Polycystic kidney disease 2-like 1(PKD2L1), previously called transient receptor potential polycystin 3 (TRPP3), forms constitutively active voltage-dependent nonselective cation channels in the plasma membrane. The mechanism of regulation of PKD2L1 channels, however, has been poorly understood. In the present study, we found a bell-shaped alkaline pH dependence of PKD2L1 channel activity at the single-channel and whole-cell levels in patch-clamp recordings in HEK293T cells overexpressing mouse PKD2L1: alkalization to pH8.0-9.0 increased the PKD2L1 currents, but alkalization to pH10.0 decreased them. Single-channel analysis revealed that alkalization changed the open probability of PKD2L1 channels, but not their single-channel conductance. In addition, the voltage dependence of PKD2L1 channels was negatively and positively shifted by treatment with solutions of pH8.0-9.0 and pH10.0, respectively. These results indicate that the voltage-dependent gating of PKD2L1 channels was modulated by alkalization through two different mechanisms. Interestingly, we observed rebound activation of the PKD2L1 channel on washout of the alkaline solution after PKD2L1 channel inhibition at pH10.0, suggesting that alkalization to pH10.0 decreased PKD2L1 currents by inactivating the channels. Consistently, the PKD2L1 tail currents were accelerated by alkalization. These results suggest that alkalization is a bimodal modulator of mouse PKD2L1 channels.

The CIL-1 PI 5-Phosphatase Localizes TRP Polycystins to Cilia and Activates Sperm in C. elegans

C. elegans male sexual behaviors include chemotaxis and response to hermaphrodites, backing, turning, vulva location, spicule insertion, and sperm transfer, culminating in cross-fertilization of hermaphrodite oocytes with male sperm. The LOV-1 and PKD-2 transient receptor potential polycystin (TRPP) complex localizes to ciliated endings of C. elegans male-specific sensory neurons and mediates several aspects of male mating behavior. TRPP complex ciliary localization and sensory function are evolutionarily conserved. A genetic screen for C. elegans mutants with PKD-2 ciliary localization (Cil) defects led to the isolation of a mutation in the cil-1 gene. Here, we report that a phosphoinositide (PI) 5-phosphatase, CIL-1, regulates TRPP complex ciliary receptor localization and sperm activation. cil-1 does not regulate the localization of other ciliary proteins, including intraflagellar transport (IFT) components, sensory receptors, or other TRP channels in different cell types. Rather, cil-1 specifically controls TRPP complex trafficking in male-specific sensory neurons and does so in a cell-autonomous fashion. In these cells, cil-1 is required for normal PI(3)P distribution, indicating that a balance between PI(3,5)P2 and PI(3)P is important for TRPP localization. cil-1 mutants are infertile because of sperm activation and motility defects. In sperm, the CIL-1 5-phosphatase and a wortmannin-sensitive PI 3-kinase act antagonistically to regulate the conversion of sessile spermatids into motile spermatozoa, implicating PI(3,4,5)P3 signaling in nematode sperm activation. Our studies identify the CIL-1 5-phosphatase as a key regulator of PI metabolism in cell types that are important in several aspects of male reproductive biology.

Regulation of the murine TRPP3 channel by voltage, pH, and changes in cell volume

Transient receptor potential (TRP) polycystin 3 (TRPP3) is a member of the TRP superfamily of cation channels. Murine TRPP3 has been reported to form an acid-activated cation channel on the plasma membrane when coexpressed with the polycystin 1-like protein 3 (PKD1L3); however, the function and biophysical properties of TRPP3-dependent channels have not yet been characterized in detail. Here we show that overexpression of murine TRPP3 channel in HEK293 cells, without coexpression of PDK1-like proteins, leads to robust channel activity. These channels exhibit a high single-channel conductance of 184 pS at negative potentials, are Ca2+-permeable, and relatively nonselective between cations. Whole-cell experiments showed a characteristic form of voltage-dependent gating of TRPP3 channels, whereby repolarization after depolarization caused large transient inward TRPP3 tail currents. Moreover, we found that TRPP3 activity was increased upon cell swelling and by alkalization. Taken together, our results demonstrate that TRPP3, on its own, can act as a voltage-dependent, pH- and volume-sensitive plasma membrane cation channel.

Identification of genes involved in the ciliary trafficking of C. elegans PKD‐2

Ciliary membrane proteins are important extracellular sensors, and defects in their localization may have profound developmental and physiological consequences. To determine how sensory receptors localize to cilia, we performed a forward genetic screen and identified 11 mutants with defects in the ciliary localization (cil) of C. elegans PKD-2, a transient receptor potential polycystin (TRPP) channel. Class A cil mutants exhibit defects in PKD-2::GFP somatodendritic localization while Class B cil mutants abnormally accumulate PKD-2::GFP in cilia. Further characterization reveals that some genes mutated in cil mutants act in a tissue-specific manner while others are likely to play more general roles in such processes as intraflagellar transport (IFT). To this end, we identified a Class B mutation that disrupts the function of the cytoplasmic dynein light intermediate chain gene xbx-1. Identification of the remaining mutations will reveal novel molecular pathways required for ciliary receptor localization and provide further insight into mechanisms of ciliary signaling.

Regulation of transient receptor potential (TRP) channels by phosphoinositides

This review summarizes the modulation of transient receptor potential (TRP) channels, by phosphoinositides. TRP channels are characterized by polymodal activation and a surprising complexity of regulation mechanisms. Possibly, most if not all TRP channels are modulated by phosphoinositides. Modulation by phosphatidylinositol 4,5-biphosphate (PIP(2)) has been shown in detail for TRP vanilloid (TRPV) 1, TRPV5, TRP melastatin (TRPM) 4, TRPM5, TRPM7, TRPM8, TRP polycystin 2, and the Drosophila TPR-like (TRPL) channels. This review describes mechanisms of modulation of TRP channels mainly by PIP(2) and discusses some future challenges of this fascinating topic.