Indirect evidence suggests that the permeability of connexin 43 (Cx43) gap-junctional channels (connexons) to small organic molecules (Mr < 1,000) is decreased by protein kinase C (PKC)-mediated phosphorylation of Ser-368. However, it is currently unknown whether this effect is produced directly by phosphorylation of this residue or whether cytoplasmic regulatory factors are required for the decrease in Cx43 gap-junctional channel permeability. Here we studied the effects of PKC-mediated phosphorylation on purified recombinant wild-type Cx43 and a PKC-unresponsive mutant (S368A). Our studies show that (a) PKC phosphorylates Ser-368, (b) the phosphorylation by PKC of purified and reconstituted connexons abolishes sucrose and Lucifer Yellow permeability, (c) the regulation of Cx43 by PKC is the direct result of phosphorylation of Ser-368 and does not involve intermediary regulatory factors, and (d) phosphorylation of Ser-368 produces a conformational change in purified Cx43 as demonstrated by changes in intrinsic Trp fluorescence and proteolytic digestion pattern. We conclude that phosphorylation of Ser-368 by PKC induces a conformational change of Cx43 that results in a decrease in connexon permeability. Indirect evidence suggests that the permeability of connexin 43 (Cx43) gap-junctional channels (connexons) to small organic molecules (Mr < 1,000) is decreased by protein kinase C (PKC)-mediated phosphorylation of Ser-368. However, it is currently unknown whether this effect is produced directly by phosphorylation of this residue or whether cytoplasmic regulatory factors are required for the decrease in Cx43 gap-junctional channel permeability. Here we studied the effects of PKC-mediated phosphorylation on purified recombinant wild-type Cx43 and a PKC-unresponsive mutant (S368A). Our studies show that (a) PKC phosphorylates Ser-368, (b) the phosphorylation by PKC of purified and reconstituted connexons abolishes sucrose and Lucifer Yellow permeability, (c) the regulation of Cx43 by PKC is the direct result of phosphorylation of Ser-368 and does not involve intermediary regulatory factors, and (d) phosphorylation of Ser-368 produces a conformational change in purified Cx43 as demonstrated by changes in intrinsic Trp fluorescence and proteolytic digestion pattern. We conclude that phosphorylation of Ser-368 by PKC induces a conformational change of Cx43 that results in a decrease in connexon permeability. Gap-junctional channels are aqueous channels responsible for cell-to-cell communication that allow for the exchange of solutes of Mr ≤ 1,000. Gap-junctional channels are formed by the docking of two connexons or gap-junctional hemichannels (GJHs) 1The abbreviations used are: GJH, gap-junctional hemichannel; Cx43, connexin 43; EGFP, enhanced green fluorescent protein; Cx43-EGFP, Cx43 with the EGFP fused to its C-terminal end; Cx43-S368A, Cx43 with Ser-368 substituted with Ala; OG, n-octyl-β-d-glucopyranoside; PMSF, phenylmethylsulfonyl fluoride; PKC, protein kinase C. , one from each neighboring cell; each connexon is formed by six connexin molecules that contain four transmembrane domains each (for a review, see Ref. 1Harris A.L. Q. Rev. Biophys. 2001; 34: 325-472Crossref PubMed Google Scholar). Cx43 is expressed in several cell types in organs such as brain, myocardium, and kidney as well as in vascular endothelial cells (2Berthoud V.M. Ledbetter M.L. Herzberg E.L. Sáez J.C. Eur. J. Cell Biol. 1992; 57: 40-50PubMed Google Scholar, 3Beyer E.C. Paul D.L. Goodenough D.A. J. Cell Biol. 1987; 105: 2621-2629Crossref PubMed Scopus (919) Google Scholar, 4Little T.L. Beyer E.C. Duling B.R. Am. J. Physiol. 1995; 37: H729-H739Google Scholar, 5Sainio K. Gilbert S.F. Lehtonen E. Nishi M. Kumar N.M. Gilula N.B. Saxen L. Development. 1992; 115: 827-837Crossref PubMed Google Scholar, 6Venance L. Premont J. Glowski J. Giaume C. J. Physiol. (Lond.). 1998; 510: 429-440Crossref Scopus (72) Google Scholar). Its functional significance in cell-to-cell communication has been clearly established (1Harris A.L. Q. Rev. Biophys. 2001; 34: 325-472Crossref PubMed Google Scholar). Cx43 GJHs have also been shown on the plasma membrane of a number of cell types (7Contreras J.E. Sánchez H. Eugenin E.A. Speidel D. Theis M. Willecke K. Bukauskas F. Bennett M.V.L. Sáez J.C. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 495-500Crossref PubMed Scopus (479) Google Scholar, 8DeVries S.H. Schwartz E.A. J. Physiol. (Lond.). 1992; 445: 201-230Crossref Scopus (241) Google Scholar, 9John S.A. Kondo R. Wang S.Y. Goldhaber J.L. Weiss J.N. J. Biol. Chem. 1999; 274: 236-240Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 10Li H. Liu T.F. Lazrak A. Peracchia C. Goldberg G.S. Lampe P.D. Johnson R.G. J. Cell Biol. 1996; 134: 1019-1030Crossref PubMed Scopus (300) Google Scholar, 11Musil L.S. Goodenough D.A. J. Cell Biol. 1991; 115: 1357-1374Crossref PubMed Scopus (617) Google Scholar, 12Kondo R.P. Wang S.W. John S.A. Weiss J.N. Goldhaber J.I. J. Mol. Cell. Cardiol. 2000; 32: 1859-1872Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 13Vergara L. Bao X. Cooper M. Bello-Reuss E. Reuss L. J. Membr. Biol. 2003; 196: 173-184Crossref PubMed Scopus (53) Google Scholar), and there is evidence supporting a role of their activation in cell injury because of uncompensated water and solute fluxes that overwhelm the normal membrane transport mechanisms, thus altering cell composition. ATP depletion may result in a decrease in the phosphorylation state of GJHs, which activates these channels, leading to cell damage (7Contreras J.E. Sánchez H. Eugenin E.A. Speidel D. Theis M. Willecke K. Bukauskas F. Bennett M.V.L. Sáez J.C. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 495-500Crossref PubMed Scopus (479) Google Scholar, 8DeVries S.H. Schwartz E.A. J. Physiol. (Lond.). 1992; 445: 201-230Crossref Scopus (241) Google Scholar, 9John S.A. Kondo R. Wang S.Y. Goldhaber J.L. Weiss J.N. J. Biol. Chem. 1999; 274: 236-240Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 12Kondo R.P. Wang S.W. John S.A. Weiss J.N. Goldhaber J.I. J. Mol. Cell. Cardiol. 2000; 32: 1859-1872Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 13Vergara L. Bao X. Cooper M. Bello-Reuss E. Reuss L. J. Membr. Biol. 2003; 196: 173-184Crossref PubMed Scopus (53) Google Scholar). It has been established that phosphorylation of specific Ser or Tyr residues in the C-terminal domain of Cx43 reduces gap-junctional intercellular communication (for reviews, see Refs. 14Lampe P.D. Lau A.F. Arch. Biochem. Biophys. 2000; 384: 205-215Crossref PubMed Scopus (471) Google Scholar and 15Lau A.F. Warn-Cramer B.J. Lin R. Peracchia C. Gap Junctions: Molecular Basis of Cell Communication in Health and Disease. Academic Press, San Diego, CA2000: 315-341Google Scholar) and that PKC phosphorylates Cx43 at Ser-368 and Ser-372 of the C-terminal domain (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar, 17Sáez J.C. Nairn A.C. Czernk A.J. Fishman G.I. Spray D.C. Hertzberg E.L. J. Mol. Cell. Cardiol. 1997; 29: 2131-2145Abstract Full Text PDF PubMed Scopus (136) Google Scholar). Recent evidence suggests that decreased phosphorylation of Cx43 at Ser-368 of the C-terminal domain increases gap-junctional channel dye permeability in cells exposed to PKC inhibitors (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar, 17Sáez J.C. Nairn A.C. Czernk A.J. Fishman G.I. Spray D.C. Hertzberg E.L. J. Mol. Cell. Cardiol. 1997; 29: 2131-2145Abstract Full Text PDF PubMed Scopus (136) Google Scholar). However, it is currently unknown whether phosphorylation of Ser-368 by PKC regulates Cx43 directly or whether this effect requires intermediary regulatory factor(s). In this context, it is believed that the decrease in Cx43 permeability produced by lowering intracellular pH, which also depends on the C-terminal domain (18Ek-Vitorin M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar, S. S. L. M. M.L. J. Biophys. J. Full Text PDF PubMed Scopus Google Scholar, M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar), requires a B.J. L. F. H. R. Gap Press, D. Scholar). studies on the regulation of Cx43 by PKC in cells are to because of the of the PKC and the of regulatory factors, we to the regulation of purified Our results purified recombinant Cx43 GJHs that phosphorylation of Ser-368 produces a conformational change that reduces permeability and that this effect does not for Cx43 for these (a) wild-type Cx43 (b) Cx43 fused to the enhanced green fluorescent protein at the C and (c) Cx43 in which Ser-368 substituted with Cx43 by the Cx43 as from see Ref. 9John S.A. Kondo R. Wang S.Y. Goldhaber J.L. Weiss J.N. J. Biol. Chem. 1999; 274: 236-240Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar) with and at the and with and to the with the EGFP by from with and for at the of the Cx43 with and to Cx43 with the to the used as a of the to the C-terminal of for for Cx43 and Cx43-EGFP, the at the C with and and the mutant by the the of the produced in cells at in with and Cell of the is shown in of the at the of of as Reuss L. Am. J. Physiol. 1996; PubMed Google Scholar) a Cx43 the Cx43 C and a of Cx43 and in cells in in of with and at at and at a of of cells by at for at with and the in used for or at cells in a and phenylmethylsulfonyl and with a as Kumar Gilula N.B. J. Cell Biol. 1991; 115: PubMed Scopus Google Scholar, Gilula N.B. J. Biol. Chem. 1987; Full Text PDF PubMed Google Scholar). of to a the with a on for and at for at In from with or in PMSF, and at a protein and for at with by at for at with of PMSF, and or OG, at a of at on a with the with of and or and in for the sucrose in the of the of of Cx43 by on these in OG, and at a of Cx43-EGFP, with or on the with the Molecular from the and the of the the as the and the and used to the and of as by J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of purified Cx43 or in OG, and with of and the for at with by the of the by Cx43 and by PKC as by Sáez J.C. Nairn A.C. Czernk A.J. Spray D.C. Hertzberg E.L. Bennett Eur. J. Biochem. PubMed Scopus Google Scholar) for with of Cx43 by PKC in the of and and the for at by of in the these Cx43 or in and to exposed at of the phosphorylation Cx43 at a of in the of of protein with for at by of a of and the and the from of the by a of and fluorescence in of the protein from the fluorescence and Cx43 the protein from with as of Cx43 and for Cx43 and a of J.M. J. 1997; PubMed Google Scholar, A.L. A. Paul D.L. Goodenough D.A. J. Mol. 1992; PubMed Scopus Google Scholar). reconstituted in a of and at a in and in of of and to it to the and a membrane for at of of a of for the transport and by the of to the for these the permeability of the purified Cx43 GJHs by the J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, A.L. A. J. J. Membr. Biol. PubMed Scopus Google Scholar, A.L. R. Giaume C. in Molecular and Press, Scholar) and by a the the a sucrose sucrose with a in on a at for at and the of the in from the to the of the fluorescence of at at In of the the with Lucifer Yellow by the fluorescent at a of the Lucifer Yellow by a Lucifer Yellow fluorescence in the at of and of sucrose by at in sucrose and specific of of the by with of a of gap-junctional channels and GJHs S. E.M. J. Membr. Biol. 2002; PubMed Scopus (136) Google Scholar, X. Reuss L. Am. J. Physiol. PubMed Scopus Google Scholar). fluorescence of Cx43 and on a with at at protein and in OG, and in shown from the with at a of of Cx43 or with at and the at by and the to In the the protein from as the protein used to the shown are by the for or of as of Cx43 in to of the fluorescence of to the for and and to whether also the for the Cx43 and for of these We that with the and that the and functional of and Cx43 in of and permeability regulation by PKC-mediated In this we the results of the and of the and that a of in cells is of Cx43 to that for the of Kumar Gilula N.B. J. Cell Biol. 1991; 115: PubMed Scopus Google Scholar). a the by and the cell fluorescence has the that it used in and is results for the of Cx43 and not also that the Cx43 purified on its for and and show that the of Cx43 is of Cx43 and of that of of that of Cx43 not purified from that not also the and functional studies have shown that gap-junctional hemichannels are of six connexin molecules (for a review, see Ref. 1Harris A.L. Q. Rev. Biophys. 2001; 34: 325-472Crossref PubMed Google Scholar). the state of the purified Cx43 we on in that the fluorescence of is with a with of the in and to the and not Cx43 to the fluorescence is with results with Cx43 in of connexons in the by of the on a sucrose not a used for the of connexin Ref. Kumar N.M. Gilula N.B. J. Cell Biol. 1997; Scholar). the results in this we conclude that Cx43 in Cx43 as connexons of the Cx43 from the Ser-368 of Cx43 by Cx43 we the permeability of GJHs reconstituted in in the and We the purified with protein by we studied and in the of phosphorylation by ATP the of phosphorylation of Cx43 by PKC by a of Cx43 and by PKC in the of It is that the phosphorylation by PKC Ser-368 substituted with results of studies show a of of and of Cx43 and Cx43-S368A, In in the of PKC Cx43 phosphorylation of the in the of decrease in phosphorylation by the and from the and is with that that Ser-368 is the phosphorylation of PKC and that phosphorylation also at Ser-372 (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar, 17Sáez J.C. Nairn A.C. Czernk A.J. Fishman G.I. Spray D.C. Hertzberg E.L. J. Mol. Cell. Cardiol. 1997; 29: 2131-2145Abstract Full Text PDF PubMed Scopus (136) Google Scholar). We have shown that changes in the phosphorylation state of Ser-372 are not in the activation of Cx43 permeability by PKC X. Reuss L. Am. J. Physiol. PubMed Scopus Google Scholar). that the decrease in in is of protein suggests that the of these Cx43 Ser-368 residues are of Ser-368 by PKC the of Cx43 studies and that the PKC that phosphorylation of Ser-368 reduces the permeability of Cx43 gap-junctional channels to small solutes (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar). However, it is not whether the effects of PKC-mediated phosphorylation are direct to phosphorylation of or by the PKC activation or regulatory factors or phosphorylation by PKC of one or whether or not the regulation of Cx43 permeability is we functional studies with purified Cx43 GJHs reconstituted Cx43 reconstituted in and by as of and the protein the for and also In Cx43 in the not from the We sucrose permeability by the of the on a a by and A.L. A. J. J. Membr. Biol. PubMed Scopus Google Scholar). has been used to sucrose permeability of and Cx43 from and J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, A.L. A. J. J. Membr. Biol. PubMed Scopus Google Scholar, A.L. R. Giaume C. in Molecular and Press, Scholar), and it is on the of with these we the with Lucifer Yellow (Mr a that connexin to transport of sucrose and Lucifer Yellow in and also to of to A.L. R. Giaume C. in Molecular and Press, Scholar, A.L. 1996; PubMed Scopus Google Scholar). of Cx43 as also Lucifer Cx43 GJHs a with of to the of the or Cx43 GJHs with the to the and the to the of the of in these is because at one connexon from the in see in a as for A.L. A. J. J. Membr. Biol. PubMed Scopus Google Scholar, A.L. R. Giaume C. in Molecular and Press, Scholar). that the Cx43 also contain Lucifer that these are not of Lucifer Yellow in the Cx43 that not with sucrose the also the Lucifer Yellow the to the of the the these results we conclude that purified Cx43 reconstituted in functional and Lucifer channels and that phosphorylation of GJHs by PKC sucrose and Lucifer Yellow fluxes thus the of Cx43 molecules that GJHs, we used the In the shown in and we reconstituted Cx43 at a of to that at one connexon the in we used Cx43 reconstituted at a of which for of that Cx43 molecules that the is and that the of a is Ref. A.L. 1996; PubMed Scopus Google Scholar). to of the and the in that of the are of the reconstituted Cx43 functional of the Cx43 is as connexons it that or of the Cx43 that as connexons in are reconstituted as functional the effects of phosphorylation on sucrose permeability we also sucrose in of that of sucrose the Cx43 in the on the Cx43 gap-junctional channel from Beyer E.C. 2002; PubMed Scopus Google Scholar), is it is not to the However, the shown in that the effect of PKC-mediated phosphorylation on sucrose permeability is or are or we the sucrose to the of Cx43 to phosphorylation by the of of of protein in the Cx43 purified of the in the and of the of the used in the of Cx43 produced a in the sucrose as from the results shown in Cx43 not permeability. are in with the shown in and the that Cx43 GJHs are to In the in show that GJHs are to sucrose of their phosphorylation the of does not or the to the results with the of the connexons in the is not a for the of transport because and phosphorylation in Cx43 and the transport of organic solutes of Mr < in and GJHs However, it is to that the sucrose reconstituted with Cx43 that by PKC of that in to the is not from that in reconstituted with Cx43 in in In the are to the are for sucrose and Lucifer Yellow and also we conclude that in Cx43 connexons Ser-368 is to the and thus that the hemichannels are the in In these Cx43 and the phosphorylation on of the these results also show that in protein the of reconstituted protein for the decreased sucrose permeability by PKC-mediated of Ser-368 a of results that Ser-368 is for the regulation of Cx43 GJHs by PKC-mediated In the of we the that phosphorylation of this residue by PKC produces a conformational change of We this in purified Cx43 in fluorescence or in that the Trp fluorescence of Cx43 in is from that of of the protein is decreased in and to a In phosphorylation of the mutant not the Trp fluorescence changes in Cx43 Trp fluorescence that one or Trp residues of Cx43 are in a the protein is We to whether the conformational changes by phosphorylation Cx43 is reconstituted in and not in the that the phosphorylation state changes the of Cx43 in Cx43 and with and the digestion by the Cx43 C-terminal results that several Cx43 the are to digestion in the the of of we the and in the of the Cx43, in the of Cx43 or of its phosphorylation state on their in a to the and and with of and to the C-terminal domain the two transmembrane of and the C-terminal domain of In this we that phosphorylation of purified Cx43 GJHs by PKC produces a conformational change in and protein and reduces the sucrose permeability of GJHs in Our that Ser-368 is the residue for these effects because the mutant is and the phosphorylation effect is direct on Cx43 the for regulatory factors because it is in purified Cx43 the of is to the that with neighboring evidence that hemichannels are at the plasma membrane of a of cells may have and (7Contreras J.E. Sánchez H. Eugenin E.A. Speidel D. Theis M. Willecke K. Bukauskas F. Bennett M.V.L. Sáez J.C. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 495-500Crossref PubMed Scopus (479) Google Scholar, 8DeVries S.H. Schwartz E.A. J. Physiol. (Lond.). 1992; 445: 201-230Crossref Scopus (241) Google Scholar, 9John S.A. Kondo R. Wang S.Y. Goldhaber J.L. Weiss J.N. J. Biol. Chem. 1999; 274: 236-240Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 12Kondo R.P. Wang S.W. John S.A. Weiss J.N. Goldhaber J.I. J. Mol. Cell. Cardiol. 2000; 32: 1859-1872Abstract Full Text PDF PubMed Scopus (170) Google Scholar, S. L. L. E. A. C. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, L. E. C. L. S. A. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. A.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of the of GJHs it is that are a for studies of the of gap-junctional channels as well as their regulation Ref. 1Harris A.L. Q. Rev. Biophys. 2001; 34: 325-472Crossref PubMed Google Scholar). to the cell it is to and reconstituted Cx43 to direct from regulatory effects of as of and Cx43 in cells has been a Kumar Gilula N.B. J. Cell Biol. 1991; 115: PubMed Scopus Google Scholar, J.M. Lau A.F. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), we the for of We also of on of and Cx43, of the Kumar Gilula N.B. J. Cell Biol. 1991; 115: PubMed Scopus Google Scholar) and of and for Kumar Gilula N.B. J. Cell Biol. 1991; 115: PubMed Scopus Google Scholar, J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) and for J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the a of in Cx43-EGFP, we to a that to of a of sucrose permeability of Cx43 reconstituted in is by phosphorylation of Ser-368 by PKC, that is to the of is effect of the the of Cx43 on its to phosphorylation because show the regulation by PKC-mediated phosphorylation of Cx43 and In the the is from the of the Cx43 the permeability of Cx43 GJHs to sucrose and Lucifer Yellow is by phosphorylation of Ser-368 in the Cx43, a result with on the permeability to of Cx43 GJHs expressed in X. Reuss L. Am. J. Physiol. PubMed Scopus Google Scholar). In we used Cx43 a and phosphorylation of Ser-368 by PKC also the hemichannels to the In the of the we that the the sucrose with the and sucrose this the (a) of Cx43 produced changes in (b) of sucrose with and with Cx43 and small with that with (c) is a solute that is not to or which is with the of sucrose to (d) direct of changes in on sucrose that the phosphorylation of Cx43 the sucrose phosphorylation studies ATP a in Cx43 and the is with the that phosphorylation of Cx43 by PKC at Ser-368 (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar, 17Sáez J.C. Nairn A.C. Czernk A.J. Fishman G.I. Spray D.C. Hertzberg E.L. J. Mol. Cell. Cardiol. 1997; 29: 2131-2145Abstract Full Text PDF PubMed Scopus (136) Google Scholar). It has been shown that PKC phosphorylates Ser-368 and and that phosphorylation of Ser-368 the permeability of gap-junctional channels (16Lampe P.D. TenBroek E.M. Burt J.M. Kurata W.E. Johnson R.G. Lau A.F. J. Cell Biol. 2000; 149: 1503-1512Crossref PubMed Scopus (470) Google Scholar). However, the as to whether the to phosphorylation by PKC requires that a to the of channels see Ref. F. J. Physiol. PubMed Scopus Google Scholar), is in the regulation of Cx43 by intracellular and protein kinase phosphorylation M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar, L. E.M. B.J. J. Cell Biol. 1999; PubMed Scopus Google Scholar). It has been that the Cx43 C which is for the as the studies on the regulation of Cx43 permeability by intracellular the of this (18Ek-Vitorin M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar, S. S. L. M. M.L. J. Biophys. J. Full Text PDF PubMed Scopus Google Scholar, M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar, M. Spray D.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), the for a intermediary has been for B.J. L. F. H. R. Gap Press, D. Scholar). It is that one or factors a regulatory are for the regulation by Our Cx43 GJHs purified and reconstituted that phosphorylation by PKC directly reduces sucrose permeability the for a regulatory protein or of the of Cx43 we also the for regulatory membrane protein has not been for the regulation by PKC-mediated In we Cx43 to the phosphorylation by PKC, the of residues is not required for the to phosphorylation by these we conclude that the effect of phosphorylation of Cx43 GJHs by PKC is it does not and is of phosphorylation by a the C-terminal domain is the may in the of Cx43 permeability by lowering intracellular and phosphorylation by protein kinase and However, the are clearly in the C-terminal domain is required for the effect of and phosphorylation by protein kinase (18Ek-Vitorin M. Biophys. J. 1996; Full Text PDF PubMed Scopus Google Scholar, L. E.M. B.J. J. Cell Biol. 1999; PubMed Scopus Google Scholar) is not in the to phosphorylation by PKC X. Reuss L. Am. J. Physiol. PubMed Scopus Google Scholar). results not in the by which PKC-mediated phosphorylation abolishes the permeability of Cx43 GJHs to organic solutes of Mr < 1,000. However, phosphorylation by PKC results in the of C-terminal that contain the C-terminal domain as well as of the is with the that phosphorylation of Ser-368 results in of the C-terminal domain with of Cx43, the intracellular as in the of Ref. M. Spray D.C. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), the of the C-terminal domain and the is that the decrease in small organic solute permeability by PKC activation of gap-junctional channels is not by a decrease in gap-junctional (for a review, see Ref. 14Lampe P.D. Lau A.F. Arch. Biochem. Biophys. 2000; 384: 205-215Crossref PubMed Scopus (471) Google Scholar). In Cx43 gap-junctional channel in with the decrease in solute permeability B.R. Cell 1995; PubMed Scopus Google Scholar). channel studies that there is a decrease in channel by in the of channel Sáez J.C. Fishman G.I. Spray D.C. PubMed Scopus Google Scholar), which for the decreased permeability to organic a of the of permeability to small solutes and phosphorylation of Cx43 fluxes of organic solutes such as and small fluxes and In this we evidence for conformational changes by phosphorylation of Cx43 as well as Our that PKC-mediated phosphorylation of Cx43, not of Cx43-S368A, produces a conformational change that Trp fluorescence and to PKC-mediated phosphorylation produces in Trp fluorescence and a of the to a effects are in Trp by PKC-mediated phosphorylation and is to that of Cx43 has six Trp residues in several of the and we the changes to specific However, the of of functional Cx43 allow to studies to the of Cx43 We that phosphorylation of Ser-368 by PKC produces a conformational change in the C-terminal domain that to a decrease in Cx43 permeability to small organic We John of at for the Cx43 for the of the and Kumar for on the
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