Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation by Inhibitor of 90-kDa Heat-Shock Protein Family: Endoplasmic Reticulum Retention of Monomeric Insulin Receptor Precursor with Calnexin in Adrenal Chromaffin Cells

Saitoh, Tomokazu; Yanagita, Toshihiko; Shiraishi, Seiji; Yokoo, Hiroki; Kobayashi, Hideyuki; Minami, Shin-ichi; Onitsuka, Toshio; Wada, Akihiko

doi:10.1124/mol.62.4.847

Cited by 25 publications

(34 citation statements)

References 40 publications

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“…If this reflects the situation in vivo, this would explain the preserved insulin action mediated by impaired insulin clearance in spite of a small reduction in the total number of insulin receptors. In cell lines transfected with other kinase-deficient INSR mutations, accelerated receptor degradation has been reported to involve heat shock protein 90 (HSP90) [33], and recently the inhibition of HSP90 was shown to reduce the levels of functional non-mutated insulin receptors on the cell surface [34]. These studies suggest that HSP90 may serve to increase the amount of non-mutated relative to mutated insulin receptors.…”

Section: Discussionmentioning

confidence: 97%

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

et al. 2006

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Aims/hypothesis Recently we reported the coexistence of postprandial hypoglycaemia and moderate insulin resistance in heterozygous carriers of the Arg1174Gln mutation in the insulin receptor gene (INSR). Controlled studies of in vivo insulin signalling in humans with mutant INSR are unavailable, and therefore the cellular mechanisms underlying insulin resistance in Arg1174Gln carriers remain to be clarified. Subjects, materials and methods We studied glucose metabolism and insulin signalling in skeletal muscle from six Arg1174Gln carriers and matched control subjects during a euglycaemic-hyperinsulinaemic clamp.Results Impaired clearance of exogenous insulin caused four-fold higher clamp insulin levels in Arg1174Gln carriers compared with control subjects (p<0.05). In Arg1174Gln carriers insulin increased glucose disposal and non-oxidative glucose metabolism (p<0.05), but to a lower extent than in controls (p<0.05). Insulin increased Akt phosphorylation at Ser473 and Thr308, inhibited glycogen synthase kinase-3α activity, reduced phosphorylation of glycogen synthase at sites 3a+3b, and increased glycogen synthase activity in Arg1174Gln carriers (all p<0.05). In the insulin-stimulated state, Akt phosphorylation at Thr308 and glycogen synthase activity were reduced in Arg1174Gln carriers compared with controls (p<0.05), whereas glycogen synthase kinase-3α activity and phosphorylation of glycogen synthase at sites 3a+3b were similar in the two groups. Conclusions/interpretation In vivo insulin signalling in skeletal muscle of patients harbouring the Arg1174Gln mutation is surprisingly intact, with modest impairments in insulin-stimulated activity of Akt and glycogen synthase explaining the moderate degree of insulin resistance. Our data suggest that impaired insulin clearance in part rescues in vivo insulin signalling in muscle in these carriers of a mutant INSR, probably by increasing insulin action on the non-mutated insulin receptors.

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Section: Discussionmentioning

confidence: 97%

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

et al. 2006

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“…Total quantities of cellular proteins, as measured by the Noninterfering Protein Assay kit, were not changed between nontreated and ketone body-treated or acidic medium-treated cells. The same amounts of proteins (7.0 -7.5 g/lane) were separated by SDS-7.5% polyacrylamide gel electrophoresis (PAGE) and transferred onto a nitrocellulose membrane; it was preincubated with 5% dry milk in phosphate-buffered saline and reacted overnight at 4°C with rabbit antibody against the C-terminal amino acid sequence (1365-1382) of the IR ␤-subunit (Cheatham and Kahn, 1995;Shiraishi et al, 2000Shiraishi et al, , 2001Yamamoto et al, 2000;Saitoh et al, 2002). After repeated washings, the immunoreactive bands were labeled with 125 I-anti-rabbit IgG (1:1000) and analyzed by a Bioimage BAS 2000 analyzer (Fuji Film, Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…Our previous study showed that chaperone function of the heat shock protein 90-kDa family was indispensable to the homodimerization of monomeric IR precursor at the ER (Saitoh et al, 2002). Protein kinase C-␣ increased IR mRNA and protein levels, thus causing up-regulation of cell surface IR (Yamamoto et al, 2000).…”

mentioning

confidence: 99%

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Yokoo

Saitoh²,

Shiraishi³

et al. 2002

J Pharmacol Exp Ther

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Treatment (м24 h) of cultured bovine adrenal chromaffin cells with ketoacidosis-related concentrations (м3 mM) of acetoacetate (but not ␤-hydroxybutyrate, acetone, and acidic medium) caused a time-and concentration-dependent reduction of cell surface 125 I-insulin binding by ϳ38%, with no change in the K d value. The reduction of 125 I-insulin binding returned to control nontreated level at 24 h after the washout of acetoacetate-treated cells. Acetoacetate did not increase the internalization rate of cell surface insulin receptor (IR), as measured in the presence of brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network. Acetoacetate (10 mM for 24 h) lowered cellular levels of the immunoreactive IR precursor molecule (ϳ190 kDa) and IR by 22 and 28%, respectively. Acetoacetate decreased IR mRNA levels by ϳ23% as early as 6 h, producing their maximum plateau reduction at 12 and 24 h. The half-life of IR mRNA was shortened by acetoacetate from 13.6 to 9.5 h. Immunoprecipitation followed by immunoblot analysis revealed that insulin-induced (100 nM for 10 min) tyrosine-phosphorylation of insulin receptor substrate-1 (IRS-1) was attenuated by 56% in acetoacetate-treated cells, with no change in IRS-1 level. These results suggest that chronic treatment with acetoacetate selectively down-regulated the density of cell surface functional IR via lowering IR mRNA levels and IR synthesis, thereby retarding insulin-induced activation of IRS-1.

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“…Some of the receptors are directed back to the plasma membrane in clatrin-coated vesicles, while others are degraded in lysosomes [3,122].…”

Section: Human Insulin Receptor's Structurementioning

confidence: 99%

“…The INSR precursor is subsequently proteolytically cleaved in trans Golgi to form the mature INSR protein which is then transported to the cell's surface [122]. The growing polypeptide chain of the insulin receptor translocates through the Sec61 translocon to the endoplasmic reticulum lumen [5].…”

Section: Human Insulin Receptor's Structurementioning

confidence: 99%

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

Rojek¹,

Niedziela²

2010

Advances in Cell Biology

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Summary:Insulin plays an important role in maintaining the whole organism's homeostasis. The presence of insulin receptors in all vertebrates and invertebrates cells reflects the diversity of regulatory processes in which this hormone is involved. Furthermore, many different factors may influence the level of insulin receptor expression. These factors include e.g. the sole insulin or stage of development. Mutations in the receptor may lead to the development of insulin resistance. These mutations differ in the level of severity and are frequently associated with diabetes mellitus, hypertension, cardiovascular disorders, heart failure, metabolic syndrome and infertility in women. More than 50 mutations in insulin receptor gene have already been characterized. These mutations are associated with rare forms of insulin resistance like leprechaunism, insulin resistance type A or Rabson-Mendenhall syndrome. Molecular analysis of insulin receptor gene may lead to a better understanding of molecular mechanisms underlying various types of insulin resistance and help to develop more efficient treatment.

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Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation by Inhibitor of 90-kDa Heat-Shock Protein Family: Endoplasmic Reticulum Retention of Monomeric Insulin Receptor Precursor with Calnexin in Adrenal Chromaffin Cells

Abstract: Treatment (Ն6 h) of cultured bovine adrenal chromaffin cells with geldanamycin (GA) or herbimycin A (HA), an inhibitor of the 90-kDa heat-shock protein (Hsp90) family, decreased cell surface 125

Cited by 25 publications

References 40 publications

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

Partial rescue of in vivo insulin signalling in skeletal muscle by impaired insulin clearance in heterozygous carriers of a mutation in the insulin receptor gene

Distinct Effects of Ketone Bodies on Down-Regulation of Cell Surface Insulin Receptor and Insulin Receptor Substrate-1 Phosphorylation in Adrenal Chromaffin Cells

Insulin Receptor and its Relationship with Different Forms of Insulin Resistance

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