Evidence for a Functional Interaction between the ClC-2 Chloride Channel and the Retrograde Motor Dynein Complex

The ClC-2 chloride channel has been implicated in essential physiological functions. Analyses of ClC-2 knock-out mice suggest that ClC-2 expression in retinal pigment epithelia and Sertoli cells normally supports the viability of photoreceptor cells and male germ cells, respectively. Further, other studies suggest that ClC-2 expression in neurons may modify inhibitory synaptic transmission via the γ-aminobutyric acid, type A receptor. However, complete understanding of the physiological functions of ClC-2 requires elucidation of the molecular basis for its regulation. Using cell imaging and biochemical and electrophysiological techniques, we show that expression of ClC-2 at the cell surface may be regulated via an interaction with the dynein motor complex. Mass spectrometry and Western blot analysis of eluate from a ClC-2 affinity matrix showed that heavy and intermediate chains of dynein bind ClC-2in vitro. The dynein intermediate chain co-immunoprecipitates with ClC-2 from hippocampal membranes suggesting that they also interact in vivo. Disruption of dynein motor function perturbs ClC-2 localization and increases the functional expression of ClC-2 in the plasma membranes of COS7 cells. Thus, cell surface expression of ClC-2 may be regulated by dynein motor activity. This work is the first to demonstrate an in vivointeraction between an ion channel and the dynein motor complex. The ClC-2 chloride channel has been implicated in essential physiological functions. Analyses of ClC-2 knock-out mice suggest that ClC-2 expression in retinal pigment epithelia and Sertoli cells normally supports the viability of photoreceptor cells and male germ cells, respectively. Further, other studies suggest that ClC-2 expression in neurons may modify inhibitory synaptic transmission via the γ-aminobutyric acid, type A receptor. However, complete understanding of the physiological functions of ClC-2 requires elucidation of the molecular basis for its regulation. Using cell imaging and biochemical and electrophysiological techniques, we show that expression of ClC-2 at the cell surface may be regulated via an interaction with the dynein motor complex. Mass spectrometry and Western blot analysis of eluate from a ClC-2 affinity matrix showed that heavy and intermediate chains of dynein bind ClC-2in vitro. The dynein intermediate chain co-immunoprecipitates with ClC-2 from hippocampal membranes suggesting that they also interact in vivo. Disruption of dynein motor function perturbs ClC-2 localization and increases the functional expression of ClC-2 in the plasma membranes of COS7 cells. Thus, cell surface expression of ClC-2 may be regulated by dynein motor activity. This work is the first to demonstrate an in vivointeraction between an ion channel and the dynein motor complex. green fluorescent protein intermediate chain dynein heavy chain dynein IC phosphate-buffered saline matrix-assisted laser desorption ionization time-of-flight erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride picoampere/picofarad ClC-2 is a member of the ClC family of chloride channels (1Jentsch T.J. Friedrich T. Schriever A. Yamada H. Pflugers Arch. 1999; 437: 783-795Crossref PubMed Scopus (291) Google Scholar). Expression of recombinant ClC-2 in Xenopus oocytes (2Thiemann A. Grunder S. Pusch M. Jentsch T.J. Nature. 1992; 356: 57-60Crossref PubMed Scopus (505) Google Scholar) and in mammalian cells (3Schwiebert E.M. Cid-Soto L.P. Stafford D. Carter M. Blaisdell C.J. Zeitlin P.L. Guggino W.B. Cutting G.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 3879-3884Crossref PubMed Scopus (128) Google Scholar) confers the expression of a hyperpolarization and swelling-activated chloride conductance path exhibiting an inwardly rectifying current-voltage relationship. Recent studies in which ClC-2 expression was disrupted in model organisms support the claim that ClC-2 directly mediates this chloride conductance. For example, a chloride conductance path with the above biophysical properties was detected in studies of salivary gland cells obtained from normal mice whereas this function was absent in salivary gland cells obtained from ClC-2 knock-out mice (4Nehrke K. Arreola J. Nguyen H.V. Pilato J. Richardson L. Okunade G. Baggs R. Shull G.E. Melvin J.E. J. Biol. Chem. 2002; 277: 23604-23611Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Similarly, depletion of theCaenorhabditis elegans ortholog of ClC-2, CLH-3, in maturing oocytes by RNA interference leads to the complete abrogation of the native, inwardly rectifying chloride conductance (5Rutledge E. Bianchi L. Christensen M. Boehmer C. Morrison R. Broslat A. Beld A.M. George A.L. Greenstein D. Strange K. Curr. Biol. 2001; 11: 161-170Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). The physiological consequences of disrupting ClC-2 expression in these organisms implicate a role for this channel at the cell surface in modifying extracellular microenvironments or cell-cell communication (5Rutledge E. Bianchi L. Christensen M. Boehmer C. Morrison R. Broslat A. Beld A.M. George A.L. Greenstein D. Strange K. Curr. Biol. 2001; 11: 161-170Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 6Bosl M.R. Stein V. Hubner C. Zdebik A.A. Jordt S.E. Mukhopadhyay A.K. Davidoff M.S. Holstein A.F. Jentsch T.J. EMBO J. 2001; 20: 1289-1299Crossref PubMed Scopus (259) Google Scholar). For example, ClC-2-deficient mice are blind, and the males are infertile. These defects have been attributed to altered chloride conductance across the plasma membrane of retinal pigment epithelium and Sertoli cells, affecting the microenvironment surrounding photoreceptors and male germ cells, respectively. Localization of ClC-2 to the apical membrane of fetal lung epithelia suggests a role in regulating airway surface fluid (7Murray C.B. Chu S. Zeitlin P.L. Am. J. Physiol. 1996; 271: L829-L837PubMed Google Scholar, 8Blaisdell C.J. Pellettieri J.P. Loughlin C.E. Chu S. Zeitlin P.L. Am. J. Respir. Cell Mol. Biol. 1999; 20: 842-847Crossref PubMed Scopus (22) Google Scholar). In addition, ClC-2 channel function has been implicated in mediating intestinal fluid secretion, as it has been localized close to the apical tight junctions of intestinal epithelia (9Gyomorey K. Yeger H. Ackerley C. Garami E. Bear C.E. Am. J. Physiol. Cell Physiol. 2000; 279: C1787-C1794Crossref PubMed Google Scholar, 10Mohammad-Panah R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Detailed studies have revealed that ClC-2 channels are also localized to intracellular vesicular compartments. Electron micrographs of immunogold-labeled ClC-2 endogenously expressed in hippocampal neurons show that it is localized not only to the plasma membrane of somata, proximal dendrites, axon initial segments but also to small transport vesicles in the cytosol (11Sik A. Smith R.L. Freund T.F. Neuroscience. 2000; 101: 51-65Crossref PubMed Scopus (92) Google Scholar). This expression pattern is similar to that described previously for the γ-aminobutyric acid, type A receptor and suggests that, as in the case of the γ-aminobutyric acid, type A receptor, the number of ClC-2 channels on the cell surface may be regulated by vesicular transport. In fact, recent studies by Bali et al. (12Bali M. Lipecka J. Edelman A. Fritsch J. Am. J. Physiol. Cell Physiol. 2001; 280: C1588-C1598Crossref PubMed Google Scholar) showed that inhibitors of phosphatidylinositol 3-kinase, a lipid kinase with a well established role in membrane trafficking, reduce the basal amplitude of ClC-2-mediated chloride currents measured by patch clamp electrophysiology on the cell surface (12Bali M. Lipecka J. Edelman A. Fritsch J. Am. J. Physiol. Cell Physiol. 2001; 280: C1588-C1598Crossref PubMed Google Scholar). These findings suggest that cell surface expression of ClC-2 may be regulated via membrane trafficking. However, as yet, little is known regarding the molecular components that regulate the cell surface expression of ClC-2. In the present study, using an integrated approach involving biochemical and cell imaging and electrophysiological techniques, we show that ClC-2 interacts with the retrograde dynein motor complexin vitro and in vivo. Further, this interaction likely mediates trafficking of ClC-2 as the subcellular and functional expression of this channel at the cell surface is disrupted by of dynein these are the first to demonstrate an in interaction between an ion channel and the dynein motor complex. The ClC-2 was by the ClC-2 that the on this the of the to the R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The for the expression of and by T. For ClC-2 was detected using a the of ClC-2. was with a the intermediate chain of dynein with and with and For and for the of the dynein heavy chain and intermediate chain and the intermediate chain However, only the analysis of hippocampal ClC-2 was detected using the or the of ClC-2 and of ClC-2, with a was as a for protein COS7 cells from the at in essential with fetal to to as well as for patch clamp on cells to with with for in with phosphate-buffered saline and for For cells with by a with in at or For cells with to and with for In cells in and with with for to protein For cells with by with in for at for with in in in for by a in to the in in for in for and in with For in by using and with a laser a The of of ClC-2 with was using a of described previously J. U. Cell PubMed Scopus Google Scholar, G. U. Cell 2000; PubMed Scopus (62) Google Scholar). was from to a this ClC-2 and The of of ClC-2 with was as the of the to the was for analysis to ClC-2 subcellular in COS7 cells. from the of the to the cell the intracellular pattern for ClC-2. This was The for was and expressed as a of and COS7 cells with a of in at to at and with on with ClC-2 dynein as described previously (9Gyomorey K. Yeger H. Ackerley C. Garami E. Bear C.E. Am. J. Physiol. Cell Physiol. 2000; 279: C1787-C1794Crossref PubMed Google Scholar). the of of the and with a transmission with a with or ClC-2, as described previously M. Li C. Garami E. Wang Y. Bear C.E. 2000; PubMed Scopus Google Scholar) in with for the of a at the was with A by was the previously with in was in in with and was at for to to the The was in and protein was with in and protein was by at the of protein S. K. Cell PubMed Scopus (62) Google Scholar, J. Cell Biol. 1999; PubMed Scopus Google Scholar, A. J. J. Mol. Biol. 1996; PubMed Scopus Google Scholar, J.P. T. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, C.J. T. J. Cell Biol. PubMed Scopus Google Scholar) and in an of protein using a from was to and For Western to the in in For of the membranes by in at for first and with to with the laser desorption ionization time-of-flight spectrometry was by the Mass at the of the protein from the ClC-2 affinity was from the with by and with of in at from the with of of by of to and with a of was with of acid, and with of A was obtained with an using as a from male as described previously J. Wang L. Wang J. PubMed Google Scholar). A membrane was obtained from with inhibitors by at for a at to and cells. For of protein from membrane in with at for at to protein and with ClC-2 for at The from with protein from with and with and for the of dynein and ClC-2. COS7 to on on for with and with for on was by cells with in with with cell by at for with for at and from with and for the of ClC-2. COS7 membrane currents measured using cell patch clamp as described previously R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). currents measured using an patch clamp and at with a was for and clamp using in a clamp a of of from to in The whereas the and and to and clamp and are as the S.E. using the obtained in patch clamp studies with and cells using the between by and between using the studies by Bali et al. (12Bali M. Lipecka J. Edelman A. Fritsch J. Am. J. Physiol. 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Sci. 2002; 11: PubMed Scopus Google Scholar). in analysis of the ClC-2 a However, not in the in or in of the from the ClC-2 of of the Recent by et al. M. Sci. 2002; 11: PubMed Scopus Google Scholar) from which was attributed to a in by with and dynein chain In fact, analysis of the revealed with molecular of M. Sci. 2002; 11: PubMed Scopus Google Scholar). is that of may have in ClC-2 of a in with other dynein that other of the dynein motor may have been as in revealed the of in the ClC-2 as a and of the in the of a protein of this vitro findings suggest that ClC-2 protein interact or with the dynein motor complex. the interaction between ClC-2 and dynein in using hippocampal membranes and the or the of ClC-2 or as a with the the is as Western of membranes from a that at that is absent in the ClC-2 knock-out by Melvin and (4Nehrke K. Arreola J. Nguyen H.V. Pilato J. Richardson L. Okunade G. Baggs R. Shull G.E. Melvin J.E. J. Biol. Chem. 2002; 277: 23604-23611Abstract Full Text Full Text PDF PubMed Scopus (97) Google hippocampal membranes and in the of as described and to and using ClC-2 the of ClC-2 be with the not ClC-2. of dynein with ClC-2 was by the described above with IC be detected in using but not in using or These findings suggest that the ClC-2 interacts with the dynein motor protein in and implicate the of ClC-2 in mediating this The biochemical described in the suggest an interaction between ClC-2 and the dynein motor complex. In the we the functional of this interaction in the COS7 as this cell endogenously ClC-2 and be micrographs of in COS7 cells revealed a pattern with a detected close to the cell surface by Electron micrographs of immunogold-labeled ClC-2 support claim that ClC-2 to the plasma membrane of COS7 cells of the of ClC-2 at the cell surface was using cell surface COS7 with to cell that not intracellular we also of the intracellular in Western analysis of from COS7 the of ClC-2 and the of this biochemical cell surface of ClC-2 endogenously expressed in COS7 cells. cell patch clamp studies the functional expression of ClC-2 at the cell of by ClC-2 with at of at and and an inwardly rectifying current-voltage was detected The a of at a membrane of that these measured currents in by ClC-2, we an have previously this approach to the functional expression of ClC-2 in cells R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google as are known of the ClC-2-mediated chloride conductance T.J. Stein V. Zdebik A.A. Physiol. 2002; PubMed Scopus Google Scholar). In this study, we showed that ClC-2 ClC-2 protein expression and This was as an chloride conductance was by ClC-2 R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). in studies in cells, we that ClC-2 of COS7 cells to of chloride currents and a in the of in cells to The of chloride currents ClC-2 that ClC-2 channels are expressed in the cell surface of COS7 cells. as in the cell studies R. Gyomorey K. Rommens J. Choudhury M. Li C. Wang Y. Bear C.E. J. Biol. Chem. 2001; 276: 8306-8313Abstract Full Text Full Text PDF PubMed Scopus (69) Google ClC-2 on chloride currents in cells in cells, that the was ClC-2 channels are expressed in the plasma membrane of COS7 cells, and this cell is for studies of vesicular trafficking to and from the plasma ClC-2 is via in COS7 cells, we the localization of ClC-2 with to a of using that the pattern of in COS7 cells at showed with in COS7 cells, in However, as ClC-2 channels may with this only we a for a known to be to but to trafficking of This has been to in the of A.L. J. Biol. Chem. Full Text PDF PubMed Google Scholar, S. K. Cell PubMed Scopus (62) Google Scholar). 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Cell Biol. 1999; PubMed Scopus Google Scholar). is in the of ClC-2 expressed at the cell surface by by at with the of of ClC-2 with in cells, these support the that ClC-2 retrograde trafficking between the plasma membrane and biochemical findings suggesting an in interaction between ClC-2 and the dynein motor are we the of disrupting and dynein motor function on ClC-2 first the subcellular of ClC-2 with that of in dynein a similar to ClC-2 with close to the cell a of ClC-2 and dynein was in proximal to the plasma membrane A and by of these at the plasma membrane was in micrographs of immunogold-labeled ClC-2 and dynein ClC-2 and dynein also to on intracellular membranes not these findings suggest a role for dynein in mediating retrograde The has been to A. J. J. Mol. 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Physiol. 1996; PubMed Scopus Google Scholar) and currents to and with ClC-2-mediated currents of a in at These are in the in E. on intestinal revealed an in ClC-2 channel function at the plasma membrane dynein with chloride currents by ClC-2 from to these findings are with that dynein may be in the vesicular transport of ClC-2. the in ClC-2 channel function of dynein function is of an in the of ClC-2 protein at the cell we the of on expression of ClC-2 in the plasma membrane by surface the of this of dynein function the of to the number of cells and the of biochemical of dynein by the of was to the of ClC-2 by These findings suggest that the in currents by of dynein function an in the of ClC-2 at the cell In the present we biochemical for vitro and in interaction between ClC-2 and dynein in we have that the dynein interact with ClC-2 protein in in vitro This interaction likely also in as dynein and ClC-2 be from hippocampal The functional consequences of this interaction in the COS7 cell using and patch clamp demonstrate that dynein is in ClC-2 trafficking, as of dynein function not only of ClC-2 subcellular localization the plasma membrane but also increases ClC-2 expression and at the cell The molecular basis the interaction between the dynein motor and ClC-2 to the the dynein motor may bind directly to ClC-2 as recent studies by al. 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