Non-selective cationic channels of smooth muscle and the mammalian homologues of Drosophila TRP

Abstract

Throughout the body there are smooth muscle cells controlling a myriad of tubes and reservoirs. The cells show enormous diversity and complexity compounded by a plasticity that is critical in physiology and disease. Over the past quarter of a century we have seen that smooth muscle cells contain--as part of a gamut of ion-handling mechanisms--a family of cationic channels with significant permeability to calcium, potassium and sodium. Several of these channels are sensors of calcium store depletion, G-protein-coupled receptor activation, membrane stretch, intracellular Ca2+, pH, phospholipid signals and other factors. Progress in understanding the channels has, however, been hampered by a paucity of specific pharmacological agents and difficulty in identifying the underlying genes. In this review we summarize current knowledge of these smooth muscle cationic channels and evaluate the hypothesis that the underlying genes are homologues of Drosophila TRP (transient receptor potential). Direct evidence exists for roles of TRPC1, TRPC4/5, TRPC6, TRPV2, TRPP1 and TRPP2, and more are likely to be added soon. Some of these TRP proteins respond to a multiplicity of activation signals--promiscuity of gating that could enable a variety of context-dependent functions. We would seem to be witnessing the first phase of the molecular delineation of these cationic channels, something that should prove a leap forward for strategies aimed at developing new selective pharmacological agents and understanding the activation mechanisms and functions of these channels in physiological systems.

Figure 1. Members of the TRP family

Single letter-code amino acid sequence alignment (Clustal W) for one of the most highly conserved region of TRPs – the distal element of the putative sixth membrane-spanning segment (S6) and the immediate C-terminus, which contains the so-called ‘TRP box’. Drosophila TRP (dTRP) is shown at the top. Thereafter, all sequences are human except for TRPC2, which is shown as mouse sequence because human TRPC2 would seem to be a pseudogene (i.e. not expressed as protein). TRPA (ANKTM1) and TRPP (polycystin) proteins show weak sequence similarity in this region and not all examples of these proteins are shown.

Figure 2. General structural themes of TRP proteins

A, hydropathy plots for TRPC1 (accession P48995) and TRPP2 (accession XP-011124) compared with Shaker voltage-gated K⁺ channel (accession P08510). A theme of six membrane-spanning segments (S1-S6) and an ion selectivity filter (P-loop) is evident in each case. TRPC1 and other TRPCs have an extra hydrophobic segment towards the N-terminus. The general S1–S6 arrangement of TRPC1 has been supported by biochemical data (Dohke et al. 2004). All sequences have been clipped at the N (left) and C (right) termini. Hydropathy (Kyte-Doolittle) plots were created using Lasergene software (DNAStar Inc.). B, diagrams of the putative membrane-spanning arrangement of TRP proteins. The upper diagram is a plan view and suggests a tetrameric arrangement with ions flowing through a central pore – as for the Shaker K⁺ channel. The lower diagram is a classical depiction of a S1–S6 protein. Extracellular targeting of antibody (Ab; not to scale) is shown for inhibition of TRPC1 function (Xu & Beech, 2001a; Beech et al. 2003; Bergdahl et al. 2003).

Figure 3. Expression of TRP mRNA species in smooth muscle cells, cell lines and whole tissue preparations

Blue, red or black filled squares indicate mRNA was detected. Under the V and M columns, numbers indicate the subtype of TRPV or TRPM. A cross indicates mRNA could not be detected in a particular study. In some cases there is conflict between results from different research groups and so filled squares and crosses are superimposed. References: (a) Xu & Beech (2001a, , Flemming et al. (2003); (b) Facemire et al. (2004); (c) Walker et al. (2001), McDaniel et al. (2001), Ng & Gurney (2001), Sweeney et al. (2002), Yu et al. (2003), Wang et al. (2004); (d) Inoue et al. (2001); (e) Facemire et al. (2003), Muraki et al. (2003); (f) Bergdahl et al. (2003); (g) Welsh et al. (2002), Earley et al. (2004), Waldron et al. (2004); (h) Jackson, et al. (2004), P. K. Jackson, B. Kumar, C. Munsch, C. D. Benham & D. J. Beech, unpublished observation; (i) Sweeney et al. (2002), Ong et al. (2003), Cloutier et al. (2003), Corteling et al. (2004), Jia et al. (2004); (j) Yang et al. (2002), Dalrymple et al. (2002), Babich et al. (2004); (k) Walker et al. (2001); (l) Lee et al. (2003); (m) Wang et al. (2003); (n) Jung et al. (2002).

Figure 4. Properties of some relevant non-selective cationic channel signals in smooth muscle

Colour coding: green, permeability; red, block; grey, no effect; blue, stimulation. ‘X’ indicates a weak effect, a mixed effect depending on the specific agent tested, or a conflict in data from different laboratories (see specific references for details). Data sets are grouped according to SOC (store-operated channel), ROC (receptor-operated channel), SAC (stretch-activated channel), CAC (Ca²⁺-activated channel), LAC (lipid-activated channel), BC (background channel). Asterisk indicates the possibility of a molecularly distinct subset of this channel type within one type of smooth muscle. References: (a) Loutzenhiser & Loutzenhiser (2000), Potocnik & Hill (2001), Curtis & Scholfield (2001), Guibert et al. (2002), Fellner & Arendshorst (2002), Flemming et al. (2002, , Curtis et al. (2003); (b) Karaki et al. (1979), Tosun et al. (1998), Samain et al. (1999), Walter et al. (2000), Tanaka et al. (2000), Trepakova et al. (2000, ; (c) Hughes & Schachter (1994), Broad et al. (1999), Iwamura et al. (1999), Patterson et al. (1999, , Moneer & Taylor (2002); (d) Casteels & Droogmans (1981), Golovina (1999), Doi et al. (2000), Golovina et al. (2001), Ng & Gurney (2001), Wilson et al. (2002), Kang et al. (2003); (e) Weirich et al. (2001); (f) Arnon et al. (2000); (g) Dreja et al. (2001); (h) Albert & Large (2002 a, ; (i) Lee et al. (2002); (j) Ohta et al. (2000); (k) Wang et al. (2003); (l) Ito et al. (2002), Sweeney et al. (2002); (m) Shlykov et al. (2003); (n) Patterson et al. (1999); (o) Broad et al. (1996); (p) Curtis & Scholfield (2001); (q) Stepien & Marche (2000); (r) Matsuoka et al. (1997); (s) Wayman et al. (1996a, , , , Wallace et al. (1999), Gibson et al. (2001), McFadzean & Gibson (2002); (t) Guibert et al. (2004); (u) Snetkov et al. (2003); (v) Byrne & Large (1988), Amédee et al. 1990, Wang & Large (1991), Kitamura et al. (1992), Inoue & Kuriyama (1993), Oike et al. (1993), Helliwell & Large (1997, , Aromolaran & Large (1999), Albert et al. (2001), Inoue et al. (2001), Large (2002), Albert & Large (2003a); (w) Van Renterghem & Lazdunski (1994), Nakajima et al. (1996), Iwasawa et al. (1997), Minowa et al. (1997), Iwamuro et al. (1998, , Kawanabe et al. (2001, , Jung et al. (2002), Moneer & Taylor (2002), Moneer et al. (2003); (x) Murray & Kotlikoff (1991), Wang & Kotlikoff (2000), Oonuma et al. (2000); (y) Amédee et al. (1990), Wang et al. (1993), Large (2002); (z) Welsh & Brayden (2001); (aa) Kim et al. (1995, , , Kang et al. (2001), Lee et al. (2003), So et al. (2003); (ab) Vogalis & Sanders (1990; (ac) Bayguinov et al. (2001); (ad) Benham et al. (1985), Inoue et al. (1987, , , , Inoue & Isenberg (1990a, , Inoue (1991), Chen et al. (1993), Zholos & Bolton (1994, , Bakhramov (1995), Shi et al. (2003), Yan et al. (2003). (ae) Guibert et al. (2004). (af) Minowa et al. (1997), Iwamuro et al. (1998, , Kawanabe et al. (2001, ; (ag) Muraki et al. (2003; (ah) Welsh et al. (2000), Slish et al. (2002; (ai) Wu & Davis (2001), Park et al. (2003), Wu et al. (2003; (aj) Wellner & Isenberg (1993a, , , Kushida et al. (2001); (ak) Loirand et al. (1991); (al) Jabr et al. (2000); (am) Terasawa et al. (2002); (an) Albert et al. (2003b); (ao) Bae et al. (1999); (ap) Zakharov et al. (1999, ; (aq) Hughes & Schachter (1994); (ar) Miyoshi et al. (2004); (as) Thorneloe & Nelson (2004).

Figure 5. Schematic diagram to illustrate how diversity might arise in TRP-dependent non-selective cationic channels

Three origins of diversity are proposed: (i) expression of multiple independent TRP genes, each with distinct properties; (ii) heteromultimerization of different TRP proteins within a tetrameric complex, with diversity arising due to differing expression levels of component TRP subunits; (iii) ‘functional modality’, by which we mean that each TRP may have the capability to be activated by several different signals (also referred to as versatility or promiscuity of gating, or multiplicity of activation). Continuous lines indicated that there is direct evidence in a smooth muscle preparation. Dotted lines indicated speculation based on work on other cell types or where evidence is not direct. See text for references and supporting information.

Figure 6. Putative local protein and signalling network associated with TRPC1

One possible heteromultimer is indicated. Homer is suggested to dissociate from inositol trisphosphate receptor (IP₃R) when stores are depleted (Yuan et al. 2003). There is evidence CIF acts on SOCs but there is no direct information for TRP (Trepakova et al. 2000; see text). References: Tsiokas et al. (1999), Lintschinger et al. (2000), Lockwich et al. (2000), Tang et al. (2000, , Trepakova et al. (2000), Strübing et al. (2001), Hofmann et al. (2002), Kunzelmann-Marche et al. (2002), Rosado et al. (2002), Singh et al. (2002), Vaca & Sampieri (2002), Beech et al. (2003), Bergdahl et al. (2003), Brazer et al. (2003), Cioffi et al. (2003), Greka et al. (2003), Ma et al. (2003), Mehta et al. (2003), Boulter et al. (2001), Qian et al. (2003b), Yuan et al. (2003), Ahmmed et al. (2004), Sinkins et al. (2004).