Elsevier

Cell Calcium

Volume 33, Issues 5–6, May–June 2003, Pages 303-310
Cell Calcium

Proteins modulating TRP channel function

https://doi.org/10.1016/S0143-4160(03)00043-5Get rights and content

Abstract

TRP channels are involved in different signaling cascades; TRP channels can be activated via hormones and neurotransmitter in a receptor/G-protein-mediated manner or by osmotic, thermic or mechanic stimuli. The overall functional role of TRP channels within these processes of hormonal cellular control, nociception or cellular calcium homeostasis is still unclear, as these complex processes often involve macromolecular structures. Whereas the integration of Drosophila TRP in the phototransduction process is becoming clear, the understanding of the participation of mammalian TRP channels in signal transduction complexes is only beginning. TRP channels have been demonstrated to interact with PDZ domain proteins, and both scaffold and regulatory function have been shown for INAD, the PDZ domain protein of the Drosophila phototransduction complex. In mammalian cells, the interaction of NHERF and TRPC4 has been shown and it is anticipated that NHERF may abolish the apparent store-dependent regulation of TRPC4 and TRPC5. Whereas TRP channels and PDZ domain proteins form permanent heterodimeric proteins, the interaction of calcium-binding proteins is dependent on the calcium concentration and is, therefore, dynamic. The prototype of calcium-binding protein used for experiments is calmodulin; whether or not calmodulin is also the natural interaction partner of TRP channels is an open question.

Introduction

Signaling of hormones across the plasma membrane is mediated by macromolecular complexes composed of different proteins (for review see [1], [2], [3]). In these macromolecular structures different proteins, i.e. receptors, channels or enzymes, are brought into vicinity to each other. The organization of proteins by structure-forming proteins speeds up the transmembrane signaling. The components of the complexes assemble directly after protein synthesis, and the proteins are translocated in preformed complexes to their cellular target compartment. The macromolecular structure is formed by scaffold proteins which share characteristic sequences. The peptide chains contain domains that mediate protein–protein interaction. Different domains important for protein–protein interaction, such as PDZ, ankyrin repeat, SH3, WW, and proline-rich domains, have been described (for review see [1], [4], [5]). The specificity of the interaction depends on the sequence of the protein domains forming the interfaces. Parallel to the permanent constituents of the complexes, additional proteins, such as calcium-binding proteins, kinases, and GTPases, can temporarily interact with single particular proteins to modulate the complex activity.

The occurrence of ankyrin repeat domains has been shown in many TRP channels [6]. Ankyrin repeat domains link proteins, i.e. inositol-1,4,5-trisphosphate (InsP3) receptor or Na+/H+-exchanger, to the cytoskeleton (for review see [7]). The occurrence of ankyrin repeat domains is differently pronounced within the three families of TRP channels. Within the members of the vanilloid-like family (TRPV), the cytosolic N-terminal sequences carry domains with the highest score of probability to function as ankyrin repeat domains, whereas this probability is reduced for the sequences of the classical TRP channel family (TRPC). In the unique N-terminal sequences of the melastatin-like subfamily (TRPM), only a few amino acids of the ankyrin repeat domain signature can be found, too little to predict an ankyrin repeat domain function. The function of the ankyrin repeat domains for TRP channels is poorly understood. Apart from that, analysis of protein sequences does not give any hints indicating that known functional domains are present in mammalian TRP channels. In contrast, the data on Drosophila phototransduction demonstrated the involvement of PDZ domains and calmodulin in TRP channel regulation (see below).

Section snippets

Calcium-binding proteins

The Drosophila TRP-like channel (TRPL) was identified in a screen searching for calmodulin-binding proteins [8]. The possible influence of calcium-binding proteins on TRP channel function results from this second cloned TRP channel, which has initially been shown to be activated following receptor/G-protein/phospholipase C (PLC) activation [9], [10], [11], [12]. Later experiments demonstrated the activation of TRPL by polyunsaturated fatty acids, whose release results from the breakdown of

PDZ domains

The name “PDZ domain” is delineated form the protein sequences of PSD-95 (protein of postsynaptic density with 95 kDa), Discs-large (Drosophila septate junction protein), and ZO-1 (protein 1 of the zona occludens) [5]. PDZ domains are formed by about 100 amino acids from which a consensus sequence of 40 amino acids has been extracted. The PDZ domains specifically bind to C-terminal sequences ending with an X-S/T-X-hydrophobic amino acid sequence. The known PDZ-binding motifs can be divided into

Structural aspects of PDZ domains in INAD for the formation of a macromolecular complex

Proteins of the Drosophila phototransduction cascade are localized in the rhabdomer, a specialized membrane compartment of the photoreceptor cells. The identification of INAD lead to the understanding that the proteins involved in phototransduction of Drosophila melanogaster are organized in a macromolecular complex [30]. INAD is composed of five PDZ domains and tethers the cation channel (TRP), phospholipase (PLC=NORPA), and an eye-specific protein kinase C (PKC=INAC). All these proteins form

Functional aspects of INAD

Many studies have clarified the proteins and sequence domains involved in protein–protein interactions. We were recently able to demonstrate functional consequences of a protein–protein interaction and, thereby, solved an old controversy on the activation mechanism of Drosophila TRP [40]. Drosophila phototransduction depends on G-protein-initiated activation of PLC and subsequent calcium entry [41], [42], [43].

In mammalian cells, G-protein-induced activation of PLC results in a release of

Mammalian INAD homologous proteins

After the mammalian TRP homologous cation channels had successfully been cloned by database searching, this approach was also used to identify mammalian INAD homologous channels. The broad distribution of PDZ domains and the presence of PDZ-sequence signatures in many proteins, however, made it very difficult to identify PDZ proteins interacting with mammalian TRP channels. A human INAD-like protein (hINADL) of 1524 amino acids comprising five PDZ domains was cloned with this approach [62].

Acknowledgements

The cDNAs were kindly provided by Reinhard Paulsen and Armin Huber (Calliphora INAD) and Andrea Zobel (Drosophila TRP). The work was supported by the Deutsche Forschungsgemeinschaft and Fonds der Chemischen Industrie.

References (83)

  • J.B. Peng et al.

    Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption

    J. Biol. Chem.

    (1999)
  • I. Bezprozvanny et al.

    Classification of PDZ domains

    FEBS Lett.

    (2001)
  • K.S. Christopherson et al.

    PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain

    J. Biol. Chem.

    (1999)
  • H. Tochio et al.

    Formation of nNOS/PSD-95 PDZ dimer requires a preformed beta-finger structure from the nNOS PDZ domain

    J. Mol. Biol.

    (2000)
  • B.H. Shieh et al.

    Regulation of the TRP Ca2+ channel by INAD in Drosophila photoreceptors

    Neuron

    (1996)
  • A. Huber et al.

    Phosphorylation of the InaD gene product, a photoreceptor membrane protein required for recovery of visual excitation

    J. Biol. Chem.

    (1996)
  • J. Chevesich et al.

    Requirement for the PDZ domain protein, INAD, for localization of the TRP store-operated channel to a signaling complex

    Neuron

    (1997)
  • B.H. Shieh et al.

    A novel protein encoded by the InaD gene regulates recovery of visual transduction in Drosophila

    Neuron

    (1995)
  • F.M. Adamski et al.

    Interaction of eye protein kinase C and INAD in Drosophila. Localization of binding domains and electrophysiological characterization of a loss of association in transgenic flies

    J. Biol. Chem.

    (1998)
  • R. Kumar et al.

    The second PDZ domain of INAD is a type I domain involved in binding to eye protein kinase C. Mutational analysis and naturally occurring variants

    J. Biol. Chem.

    (2001)
  • B.T. Bloomquist et al.

    Isolation of a putative phospholipase C gene of Drosophila, norpA, and its role in phototransduction

    Cell

    (1988)
  • K. Mikoshiba et al.

    Structure and function of IP3 receptors

    Semin. Cell Biol.

    (1994)
  • S. Patel et al.

    Molecular properties of inositol 1,4,5-trisphosphate receptors

    Cell Calcium

    (1999)
  • J.W. Putney

    A model for receptor-regulated calcium entry

    Cell Calcium

    (1986)
  • M.D. Bootman et al.

    Calcium signalling—an overview

    Semin. Cell Dev. Biol.

    (2001)
  • C. Zitt et al.

    Cloning and functional expression of a human Ca2+-permeable cation channel activated by calcium store depletion

    Neuron

    (1996)
  • X.Z. Xu et al.

    Coassembly of TRP and TRPL produces a distinct store-operated conductance

    Cell

    (1997)
  • J. Lytton et al.

    Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps

    J. Biol. Chem.

    (1991)
  • R. Ranganathan et al.

    Cytosolic calcium transients: spatial localization and role in Drosophila photoreceptor cell function

    Neuron

    (1994)
  • R.C. Hardie

    Excitation of Drosophila photoreceptors by BAPTA and ionomycin: evidence for capacitative Ca2+ entry?

    Cell Calcium

    (1996)
  • J.K. Acharya et al.

    InsP3 receptor is essential for growth and differentiation but not for vision in Drosophila

    Neuron

    (1997)
  • P. Raghu et al.

    Normal phototransduction in Drosophila photoreceptors lacking an InsP3 receptor gene

    Mol. Cell. Neurosci.

    (2000)
  • S. Philipp et al.

    Molecular characterization of a novel human PDZ domain protein with homology to INAD from Drosophila melanogaster

    FEBS Lett.

    (1997)
  • P. Vaccaro et al.

    Distinct binding specificity of the multiple PDZ domains of INADL, a human protein with homology to INAD from Drosophila melanogaster

    J. Biol. Chem.

    (2001)
  • C. Lemmers et al.

    hINADl/PATJ, a homolog of discs lost, interacts with crumbs and localizes to tight junctions in human epithelial cells

    J. Biol. Chem.

    (2002)
  • S. Wang et al.

    Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)

    FEBS Lett.

    (1998)
  • T. Okada et al.

    Molecular cloning and functional characterization of a novel receptor-activated TRP Ca2+ channel from mouse brain

    J. Biol. Chem.

    (1998)
  • M. Schaefer et al.

    Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5

    J. Biol. Chem.

    (2000)
  • A.G. Obukhov et al.

    TRPC4 can be activated by G-protein-coupled receptors and provides sufficient Ca2+ to trigger exocytosis in neuroendocrine cells

    J. Biol. Chem.

    (2002)
  • M. Schaefer et al.

    Functional differences between TRPC4 splice variants

    J. Biol. Chem.

    (2002)
  • Y. Tang et al.

    Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF

    J. Biol. Chem.

    (2000)
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