Caveolin-3 and SAP97 form a scaffolding protein complex that regulates the voltage-gated potassium channel Kv1.5

Folco, Eduardo J.; Liu, Gong-Xin; Koren, Gideon

doi:10.1152/ajpheart.00152.2004

Cited by 57 publications

(53 citation statements)

References 31 publications

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“…Folding and assembly efficiencies, controlled by chaperon-like proteins such as calnexin or ␤ subunits, could determine this variation (31,34). In addition, several ER retention signals within the pore and C-and N-terminal domains determine traffic and surface expression (29). Although VXXSL in the C terminus is considered a strong ER export motif, neither Kv1.3 nor Kv1.5 shares this element.…”

Section: Discussionmentioning

confidence: 99%

“…For instance, Kv1.3 targets to different rafts upon activation and apoptosis in lymphocytes (16,28). Disruption of these domains alters channel activity, and raft association seems to be dynamic (15,17,18,29,38). Scaffolding proteins like membrane-associated guanylate kinases are involved in the K ϩ channel association with raft domains.…”

Section: Discussionmentioning

confidence: 99%

“…Scaffolding proteins like membrane-associated guanylate kinases are involved in the K ϩ channel association with raft domains. This is the case of PSD-95 for Kv1.4 or SAP97 for Kv1.5 (29,38,39). In addition, Kv1.5 targets to caveolae without an apparent physical association (23), but it forms macromolecular complexes with SAP97 and caveolin-3 (29).…”

Section: Discussionmentioning

confidence: 99%

“…Changes in this distribution, such as different lipid raft populations, determine different spatial regulations affecting the function (17,18). Although Kv1.3 targets to lipid rafts, Kv1.5 localization is uncertain (16,23,29,30). Therefore we wanted to study whether Kv1.3 and Kv1.3/Kv1.5 heteromers target to these domains.…”

Section: Kv13 and Kv15 Localize To Different Intracellularmentioning

confidence: 99%

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Kv1.5 Association Modifies Kv1.3 Traffic and Membrane Localization

Vicente

Villalonga

Calvo

et al. 2008

Journal of Biological Chemistry

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Kv1.3 activity is determined by raft association. In addition to Kv1.3, leukocytes also express Kv1.5, and both channels control physiological responses. Because the oligomeric composition may modify the channel targeting to the membrane, we investigated heterotetrameric Kv1.3/Kv1.5 channel traffic and targeting in HEK cells. Kv1.3 and Kv1.5 generate multiple heterotetramers with differential surface expression according to the subunit composition. FRET analysis and pharmacology confirm the presence of functional hybrid channels. Raft association was evaluated by cholesterol depletion, caveolae colocalization, and lateral diffusion at the cell surface. Immunoprecipitation showed that both Kv1.3 and heteromeric channels associate with caveolar raft domains. However, homomeric Kv1.3 channels showed higher association with caveolin traffic. Moreover, FRAP analysis revealed higher mobility for hybrid Kv1.3/Kv1.5 than Kv1.3 homotetramers, suggesting that heteromers target to distinct surface microdomains. Studies with lipopolysaccharide-activated macrophages further supported that different physiological mechanisms govern Kv1.3 and Kv1.5 targeting to rafts. Our results implicate the traffic and localization of Kv1.3/Kv1.5 heteromers in the complex regulation of immune system cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Kv13 and Kv15 Localize To Different Intracellularmentioning

confidence: 99%

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Kv1.5 Association Modifies Kv1.3 Traffic and Membrane Localization

Vicente

Villalonga

Calvo

et al. 2008

Journal of Biological Chemistry

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“…SAP97 was coprecipitated with full-length Sec8, but not with a mutant Sec8 lacking a PDZ-binding motif in its C-terminus (Sec8-⌬4aa) ( Figure 5A), verifying that SAP97 binds to Sec8 through the PDZ-binding motif in the C-terminus. SAP97 is reportedly expressed in lipid rafts in muscle cells (Folco et al, 2004). We explored the localization of SAP97 in 3T3L1 adipocytes by both immunostaining and sucrose density gradient fractionation.…”

Section: Sap97 Anchors the Exocyst Complex To Lipid Raftsmentioning

confidence: 99%

Compartmentalization of the Exocyst Complex in Lipid Rafts Controls Glut4 Vesicle Tethering

Inoue

Chiang

Chang

et al. 2006

MBoC

108

135

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Lipid raft microdomains act as organizing centers for signal transduction. We report here that the exocyst complex, consisting of Exo70, Sec6, and Sec8, regulates the compartmentalization of Glut4-containing vesicles at lipid raft domains in adipocytes. Exo70 is recruited by the G protein TC10 after activation by insulin and brings with it Sec6 and Sec8. Knockdowns of these proteins block insulin-stimulated glucose uptake. Moreover, their targeting to lipid rafts is required for glucose uptake and Glut4 docking at the plasma membrane. The assembly of this complex also requires the PDZ domain protein SAP97, a member of the MAGUKs family, which binds to Sec8 upon its translocation to the lipid raft. Exocyst assembly at lipid rafts sets up targeting sites for Glut4 vesicles, which transiently associate with these microdomains upon stimulation of cells with insulin. These results suggest that the TC10/exocyst complex/SAP97 axis plays an important role in the tethering of Glut4 vesicles to the plasma membrane in adipocytes. INTRODUCTIONInsulin stimulates glucose transport in fat and muscle cells through a process of regulated vesicle recycling in which the facilitative glucose transporter Glut4 is translocated from intracellular sites to the plasma membrane (Saltiel and Kahn, 2001;Bryant et al., 2002). In unstimulated cells, Glut4 undergoes endocytosis into endosomes and subsequently sorts into specialized storage vesicles that traffic to the plasma membrane after activation of the insulin receptor. The vesicles then dock and fuse at specific sites at the membrane, resulting in extracellular exposure of the transporter. The precise signals from the insulin receptor that control these events involve the tyrosine phosphorylation of a number of intracellular substrates. These phosphorylations lead to activation of the PI3-kinase pathway (Saltiel and Kahn, 2001) and also to activation of the G protein TC10 Maffucci et al., 2003), which in turn binds to numerous effectors, including the exocyst protein Exo70 (Inoue et al., 2003). Exo70 exists in a multiprotein complex with the proteins Sec6 and Sec8. A dominant-negative mutant of Exo70 blocked insulin-stimulated glucose uptake, but was without effect on translocation of Glut4 to the plasma membrane. However, this Exo70 mutant prevented the appearance of Glut4 at the cell surface, leading us to propose that the exocyst complex may play a critical role in tethering Glut4 vesicles to the plasma membrane for subsequent docking and fusion (Inoue et al., 2003).Lipid rafts are specialized compartments of the plasma membrane enriched in cholesterol and glycosphingolipids. Numerous signaling and cytoskeletal proteins are found in these subdomains, suggesting that they may act as organizing centers for signal transduction, particularly for insulin (Anderson, 1998;Schlegel et al., 1998;Bickel, 2002; Pessin, 2002, 2003). Both the insulin receptor and TC10 reside in lipid rafts (Yamamoto et al., 1998;Gustavsson et al., 1999;Nystrom et al., 1999;Kimura et al., 2002;Vainio et al., 2002)...

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