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PubMed2006

Subcellular translocation of the eGFP-tagged TRPL channel in Drosophila photoreceptors requires activation of the phototransduction cascade.

Signal-mediated translocation of transient receptor potential (TRP) channels is a novel mechanism to fine tune a variety of signaling pathways including neuronal path finding and Drosophila photoreception. In Drosophila phototransduction the cation channels TRP and TRP-like (TRPL) are the targets of a prototypical G protein-coupled signaling pathway. We have recently found that the TRPL channel translocates between the rhabdomere and the cell body in a light-dependent manner. This translocation modifies the ion channel composition of the signaling membrane and induces long-term adaptation. However, the molecular mechanism underlying TRPL translocation remains unclear. Here we report that eGFP-tagged TRPL expressed in the photoreceptor cells formed functional ion channels with properties of the native channels, whereas TRPL-eGFP translocation could be directly visualized in intact eyes. TRPL-eGFP failed to translocate to the cell body in flies carrying severe mutations in essential phototransduction proteins, including rhodopsin, Galphaq, phospholipase Cbeta and the TRP ion channel, or in proteins required for TRP function. Our data, furthermore, show that the activation of a small fraction of rhodopsin and of residual amounts of the Gq protein is sufficient to trigger TRPL-eGFP internalization. In addition, we found that endocytosis of TRPL-eGFP occurs independently of dynamin, whereas a mutation of the unconventional myosin III, NINAC, hinders complete translocation of TRPL-eGFP to the cell body. Altogether, this study revealed that activation of the phototransduction cascade is mandatory for TRPL internalization, suggesting a critical role for the light induced conductance increase and the ensuing Ca2+ -influx in the translocation process. The critical role of Ca2+ influx was directly demonstrated when the light-induced TRPL-eGFP translocation was blocked by removing extracellular Ca2+.

Animals↗
PubMed2005

Mechanisms of light adaptation in Drosophila photoreceptors.

Phototransduction in Drosophila is mediated by a phospholipase C (PLC) cascade culminating in activation of transient receptor potential (TRP) channels. Ca(2+) influx via these channels is required for light adaptation, but although several molecular targets of Ca(2+)-dependent feedback have been identified, their contribution to adaptation is unclear. By manipulating cytosolic Ca(2+) via the Na(+)/Ca(2+) exchange equilibrium, we found that Ca(2+) inhibited the light-induced current (LIC) over a range corresponding to steady-state light-adapted Ca(2+) levels (0.1-10 microM Ca(2+)) and accurately mimicked light adaptation. However, PLC activity monitored with genetically targeted PIP(2)-sensitive ion channels (Kir2.1) was first inhibited by much higher (>/= approximately 50 microM) Ca(2+) levels, which occur only transiently in vivo. Ca(2+)-dependent inhibition of PLC, but not the LIC, was impaired in mutants (inaC) of protein kinase C (PKC). The results indicate that light adaptation is primarily mediated downstream of PLC and independently of PKC by Ca(2+)-dependent inhibition of TRP channels. This is interpreted as a strategy to prevent inhibition of PLC by global steady-state light-adapted Ca(2+) levels, whereas rapid inhibition of PLC by local Ca(2+) transients is required to terminate the response and ensures that PIP(2) reserves are not depleted during stimulation.

Adaptation, Ocular↗
PubMed2005

Anandamide as an intracellular messenger regulating ion channel activity.

The endocannabinoid anandamide (N-arachidonoylethanolamine) was proposed to be an extracellular retrograde messenger, which regulates excitability of neurons by cannabinoid CB1 receptor-dependent inhibition of neurotransmitter release. Recent findings indicate that the neuromodulatory actions of anandamide might be more complex. Anandamide has been shown to directly modulate various ion channels, such as alpha7-nicotinic acetylcholine receptors, T-type Ca2+ channels, voltage-gated and background K+-channels and Transient Receptor Potential Vanilloid type 1 (TRPV1) channels. The binding site of anandamide at some of these ion channels appears to be intracellular or at the bilayer interface. This rises the intriguing possibility that anandamide, prior to its release into the synaptic cleft, may regulate ion homeostasis and excitability of neurons as an intracellular modulator of ion channels independent of its action at cannabinoid CB1 receptors. This possibility might extend the concept of anandamide as an endocannabinoid retrograde messenger and may have profound implications for its role in neurotransmission and neuronal function. Here, we will review the evidence for this hypothesis.

Animals↗
PubMed2005

Functionality of the TRPV subfamily of TRP ion channels: add mechano-TRP and osmo-TRP to the lexicon!

Transient receptor potential (TRP) ion channels have been identified as cellular sensors responding to diverse external and internal stimuli. This review will cover the TRPV subfamily that comprises vertebrate and invertebrate members. The six mammalian TRPV channels were demonstrated to function in thermosensation, mechanosensation, osmosensation and Ca(2+) uptake. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic and chemical stimuli in C. elegans. We will focus here on the role that TRPV ion channels play in mechanosensation and a related sensory (sub-)modality, osmosensation.

Animals↗
PubMed2006

Posttranslational cleavage and adaptor protein complex-dependent trafficking of mucolipin-1.

Mucolipin-1 (ML1) is a member of the transient receptor potential ion channel superfamily that is thought to function in the biogenesis of lysosomes. Mutations in ML1 result in mucolipidosis type IV, a lysosomal storage disease characterized by the intracellular accumulation of enlarged vacuolar structures containing phospholipids, sphingolipids, and mucopolysaccharides. Little is known about how ML1 trafficking or activity is regulated. Here we have examined the processing and trafficking of ML1 in a variety of cell types. We find that a significant fraction of ML1 undergoes cell type-independent cleavage within the first extracellular loop of the protein during a late step in its biosynthetic delivery. To determine the trafficking route of ML1, we systematically examined the effect of ablating adaptor protein complexes on the localization of this protein. Whereas ML1 trafficking was not apparently affected in fibroblasts from mocha mice that lack functional adaptor protein complex (AP)-3, small interfering RNA-mediated knockdown revealed a requirement for AP-1 in Golgi export of ML1. Knockdown of functional AP-2 had no effect on ML1 localization. Interestingly, cleavage of ML1 was not compromised in AP-1-deficient cells, suggesting that proteolysis occurs in a prelysosomal compartment, possibly the trans-Golgi network. Our results suggest that posttranslational processing of ML1 is more complex than previously described and that this protein is delivered to lysosomes primarily via an AP-1-dependent route that does not involve passage via the cell surface.

Animals↗
PubMedDate not supplied

The venerable inveterate invertebrate TRP channels.

The transient receptor potential (TRP) superfamily is subdivided into four main classes of cation channels, TRPC, TRPV, TRPM and TRPN, each of which includes members in worms, flies, mice and humans. While the biophysical features of many of the mammalian channels have been described, relatively little is known concerning the biological roles of these channels. Forward genetic screens in Drosophila melanogaster and Caenorhabditis elegans have led to the identification of the founding members of each of these four subfamilies. Moreover, phenotypic analyses of invertebrate mutants have contributed greatly to our understanding of the roles of TRP proteins. A recurring theme is that many of these proteins function in sensory signaling processes ranging from vision to olfaction, osmosensation, light touch, social feeding, and temperature- and mechanically-induced nociception. In addition, at least one invertebrate TRP protein is required for cell division. As many of these functions may be conserved among the mammalian TRPs, the invertebrate TRPs offer valuable genetic handles for characterizing the functions of these cation channels in vivo.

Animals↗
PubMed2000

Phenotypes of trpl mutants and interactions between the transient receptor potential (TRP) and TRP-like channels in Drosophila.

The trp and trpl genes are thought to encode two classes of light-activated ion channels in Drosophila. A previous report indicated that a null trpl mutant does not display any mutant phenotype. This lack of detectable mutant phenotypes made it difficult to suggest functions for the transient receptor potential-like (TRPL) channel in photoreceptor responses. Here, the properties of trpl photoreceptor responses were studied by using electroretinogram (ERG) and intracellular recording techniques in combination with light stimuli of relatively long durations. Distinct mutant phenotypes were detectable under these conditions. These consisted of a reduced sustained component, oscillations superimposed on the response, a poststimulus hyperpolarization, and altered adaptation properties to dim background light. Comparison of photoreceptor responses obtained from wild type, trp, and trpl showed that the responses obtained from the trp and trpl null mutants did not sum up to that of the wild-type response. To explain the nonlinear summation at the peak of the response, Reuss et al. (1997) proposed that Ca(2+) ions entering through the TRP channel modulate TRP and TRPL channel activities differentially. However, nonlinear summation was present not only at the peak but throughout the duration of response. Two lines of evidence are presented to suggest that, in addition to the interaction proposed by Reuss et al. (1997), there are other forms of interactions between TRP and TRPL channels, probably involving the channel proteins themselves.

Amino Acid Substitution↗
PubMed2005

TRP-ML1 is a lysosomal monovalent cation channel that undergoes proteolytic cleavage.

Mutations in the gene MCOLN1 coding for the TRP (transient receptor potential) family ion channel TRP-ML1 lead to the lipid storage disorder mucolipidosis type IV (MLIV). The function and role of TRP-ML1 are not well understood. We report here that TRP-ML1 is a lysosomal monovalent cation channel. Both native and recombinant TRP-ML1 are cleaved resulting in two products. Recombinant TRP-ML1 is detected as the full-length form and as short N- and C-terminal forms, whereas in native cells mainly the cleaved N and C termini are detected. The N- and C-terminal fragments of TRP-ML1 were co-immunoprecipitated from cell lysates and co-eluted from a Ni2+ column. TRP-ML1 undergoes proteolytic cleavage that is inhibited by inhibitors of cathepsin B (CatB) and is altered when TRP-ML1 is expressed in CatB-/- cells. N-terminal sequencing of purified C-terminal fragment of TRP-ML1 expressed in Sf9 cells indicates a cleavage site at Arg200 downward arrow Pro201. Consequently, the conserved R200H mutation changed the cleavage pattern of TRP-ML1. The cleavage inhibited TRP-ML1 channel activity. This work provides the first example of inactivation by cleavage of a TRP channel. The significance of the cleavage to the function of TRP-ML1 is under investigation.

Animals↗
PubMed2005

Differential expression and molecular characterisation of Lmo7, Myo1e, Sash1, and Mcoln2 genes in Btk-defective B-cells.

PURPOSE: Bruton's tyrosine kinase is crucial for B-lymphocyte development. By the use of gene expression profiling, we have identified four expressed sequence tags among 38 potential Btk target genes, which have now been characterised. METHODS: Bioinformatics tools including data mining of additional unpublished gene expression profiles, sequence verification of PCR products and qualitative RT-PCR were used. Stimulations targeting the B-cell receptor and the protein kinase C were used to activate whole B-cell splenocytes. RESULTS: Target genes were characterised as Lim domain only 7 (Lmo7); Myosin1e (Myo1e); SAM and SH3 domain containing 1 (Sash1); and Mucolipin2 (Mcoln2). Expression was found in cell lines of different origin and developmental stages as well as in whole B-cell splenocytes and Transitional type 1 (T1) splenic B-cells from wild type and Btk-defective mice, respectively. By the use of semi-quantitative RT-PCR we found Sash1 not to be expressed in the investigated haematopoietic cell lines, while transcripts were found in whole splenic B-cells from both wild type and Btk-defective mice, whereas Lmo7, Myo1e, and Mcoln2 were expressed in both B-cell lines and primary B-lymphocytes. Except for Lmo7, the transcript level was similarly affected by stimulation in control and Btk-defective cells.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2001

The TRP ion channel family.

Mammalian homologues of the Drosophila transient receptor potential (TRP) channel gene encode a family of at least 20 ion channel proteins. They are widely distributed in mammalian tissues, but their specific physiological functions are largely unknown. A common theme that links the TRP channels is their activation or modulation by phosphatidylinositol signal transduction pathways. The channel subunits have six transmembrane domains that most probably assemble into tetramers to form non-selective cationic channels, which allow for the influx of calcium ions into cells. Three subgroups comprise the TRP channel family; the best understood of these mediates responses to painful stimuli. Other proposed functions include repletion of intracellular calcium stores, receptor-mediated excitation and modulation of the cell cycle.

Animals↗
PubMed2007

Assembly domains in TRP channels.

The large family of mammalian TRP (transient receptor potential) ion channels encompasses diverse sensory functions. TRP proteins consist of six transmembrane domains, with a pore-loop motif between the fifth and sixth domains and cytosolic N- and C-termini. The intracellular strands not only interact with various proteins and lipids, but also include essential multimerization regions. This review summarizes the current knowledge of the intrinsic assembly domains that assure tetrameric TRP channel formation.

Amino Acid Motifs↗
PubMed2006

Insights on TRP channels from in vivo studies in Drosophila.

Transient receptor potential (TRP) channels mediate responses in a large variety of signaling mechanisms. Most studies on mammalian TRP channels rely on heterologous expression, but their relevance to in vivo tissues is not entirely clear. In contrast, Drosophila TRP and TRP-like (TRPL) channels allow direct analyses of in vivo function. In Drosophila photoreceptors, activation of TRP and TRPL is mediated via the phosphoinositide cascade, with both Ca2+ and diacylglycerol (DAG) essential for generating the light response. In tissue culture cells, TRPL channels are constitutively active, and lipid second messengers greatly facilitate this activity. Inhibition of phospholipase C (PLC) completely blocks lipid activation of TRPL, suggesting that lipid activation is mediated via PLC. In vivo studies in mutant Drosophila also reveal an acute requirement for lipid-producing enzyme, which may regulate PLC activity. Thus, PLC and its downstream second messengers, Ca2+ and DAG, constitute critical mediators of TRP/TRPL gating in vivo.

Animals↗
PubMed2001

A physical and transcript map of the MCOLN1 gene region on human chromosome 19p13.3-p13.2.

Mutations in MCOLN1 have been found to cause mucolipidosis type IV (MLIV; MIM 252650), a rare autosomal recessive lysosomal storage disorder found primarily in the Ashkenazi Jewish population. As a part of the successful cloning of MCOLN1, we constructed a 1.4-Mb physical map containing 14 BACs and 4 cosmids that encompasses the region surrounding MCOLN1 on human chromosome 19p13.3-p13.2-a region to which linkage or association has been reported for multiple diseases. Here we detail the precise physical mapping of 28 expressed sequence tags that represent unique UniGene clusters, of which 15 are known genes. We present a detailed transcript map of the MCOLN1 gene region that includes the genes KIAA0521, neuropathy target esterase (NTE), a novel zinc finger gene, and two novel transcripts in addition to MCOLN1. We also report the identification of eight new polymorphic markers between D19S406 and D19S912, which allowed us to pinpoint the location of MCOLN1 by haplotype analysis and which will facilitate future fine-mapping in this region. Additionally, we briefly describe the correlation between the observed haplotypes and the mutations found in MCOLN1. The complete 14-marker haplotypes of non-Jewish disease chromosomes, which are crucial for the genetic diagnosis of MLIV in the non-Jewish population, are presented here for the first time.

Chromosome Mapping↗
PubMed2006

Role of intracellular stores in the regulation of rhythmical [Ca2+]i changes in interstitial cells of Cajal from rabbit portal vein.

Interstitial cells of Cajal (ICCs) freshly isolated from rabbit portal vein and loaded with the Ca(2+)-sensitive indicator fluo-3 revealed rhythmical [Ca(2+)](i) changes occurring at 0.02-0.1 Hz. Each increase in [Ca(2+)](i) originated from a discrete central region of the ICC and propagated as a [Ca(2+)](i) wave towards the cell periphery, but usually became attenuated before reaching the ends of the cell. In about 40% of ICCs each rhythmical change in [Ca(2+)](i) consisted of an initial [Ca(2+)](i) increase (phase 1) followed by a faster rise in [Ca(2+)](i) (phase 2) and then a decrease in [Ca(2+)](i) (phase 3); the frequency correlated with the rate of rise of [Ca(2+)](i) during phase 1, but not with the peak amplitude. Rhythmical [Ca(2+)](i) changes persisted in nicardipine, but were abolished in Ca(2+)-free solution as well as by SK&F96365, cyclopiazonic acid, thapsigargin, 2-APB, xestospongin C or ryanodine. Intracellular Ca(2+) stores visualised with the low-affinity Ca(2+) indicator fluo-3FF were found to be enriched with ryanodine receptors (RyRs) detected with BODIPY TR-X ryanodine. Rhythmical [Ca(2+)](i) changes originated from a perinuclear S/ER element showing the highest RyR density. Immunostaining with anti-TRPC3,6,7 antibodies revealed the expression of these channel proteins in the ICC plasmalemma. This suggests that these rhythmical [Ca(2+)](i) changes, a key element of ICC pacemaking activity, result from S/ER Ca(2+) release which is mediated via RyRs and IP(3) receptors and is modulated by the activity of S/ER-Ca(2+)-ATPase and TRP channels but not by L-type Ca(2+) channels.

Animals↗
PubMed2006

Behavioral motifs and neural pathways coordinating O2 responses and aggregation in C. elegans.

BACKGROUND: Simple stimuli can evoke complex behavioral responses coordinated by multiple neural circuits. O(2) is an important environmental variable for most animals. The nematode C. elegans avoids high O(2), and O(2) levels regulate its foraging and aggregation. RESULTS: Here, we dissect aggregation and responses to O(2) gradients into behavioral motifs and show how O(2) responses can promote aggregation. To remain in a group, C. elegans continually modify their movement. Animals whose heads emerge from a group will reverse or turn, thereby returning to the group. Re-entry inhibits further reversal, aiding retention in the group. If an animal's tail exits a group during a reversal, it switches to forward movement, returning to the group. Aggregating C. elegans locally deplete O(2). The rise in O(2) levels experienced by animals leaving a group induces both reversal and turning. Conversely, the fall in O(2) encountered when entering a clump suppresses reversal, turning, and high locomotory activity. The soluble guanylate cyclases GCY-35 and GCY-36, which are expressed in head and tail neurons, promote reversal and turning when O(2) rises. Avoidance of high O(2) is also promoted by the TRP-related channel subunits OCR-2 and OSM-9, and the transmembrane protein ODR-4, acting in the nociceptive neurons ASH and ADL. Both O(2) responsiveness and aggregation can be modified by starvation, but this is regulated by natural variation in the npr-1 neuropeptide receptor. CONCLUSIONS: Our work provides insights into how a complex behavior emerges from simpler behavioral motifs coordinated by a distributed circuit.

Animals↗
PubMed2006

Roles of CRAC and Cav-like channels in T cells: more than one gatekeeper?

Ca2+ channels in the plasma membrane of T cells vitally influence Ca2+-dependent signals that lead ultimately to cytokine secretion, cellular proliferation and apoptosis. Conventional models depict the Ca2+ inrush across the T-cell membrane following T-cell receptor engagement as being due to Ca2+-release-activated Ca2+ (CRAC) channels. A poorly understood mechanism detects the lowered Ca2+ concentrations within intracellular stores that open CRAC channels. Mammalian homologs of the Drosophila transient receptor potential Ca2+ channels possibly help to gate the store-operated, Ca2+-borne CRAC current. In this article, we review evidence of a supplementary involvement of other Ca2+ channels, the opening of which does not necessarily reflect intracellular Ca2+-store depletion. We highlight a role for variants of L-type voltage-dependent Ca2+ channels in increasing intracellular Ca2+ concentrations during activation. For more-accurate modeling of lymphocyte activation and possible pharmacological interventions, future research should aim to identify physiologically relevant situations in which such channels help to shape the Ca2+ signal.

Animals↗