Insulin induces calcium signals in the nucleus of rat hepatocytes.
Insulin is an hepatic mitogen that promotes liver regeneration. Actions of insulin are mediated by the insulin receptor, which is a receptor tyrosine kinase. It is currently thought that signaling via the insulin receptor occurs at the plasma membrane, where it binds to insulin. Here we report that insulin induces calcium oscillations in isolated rat hepatocytes, and that these calcium signals depend upon activation of phospholipase C and the inositol 1,4,5-trisphosphate receptor, but not upon extracellular calcium. Furthermore, insulin-induced calcium signals occur in the nucleus, and are temporally associated with selective depletion of nuclear phosphatidylinositol bisphosphate and translocation of the insulin receptor to the nucleus. These findings suggest that the insulin receptor translocates to the nucleus to initiate nuclear, inositol 1,4,5-trisphosphate-mediated calcium signals in rat hepatocytes. This novel signaling mechanism may be responsible for insulin's effects on liver growth and regeneration.
Rodrigues
Michele A
MA
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8019, USA.
Gomes
Dawidson A
DA
Andrade
Viviane A
VA
Leite
M Fatima
MF
Nathanson
Michael H
MH
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000502:physiology; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D007328:Insulin; D019269:Phosphatidylinositol 4,5-Diphosphate; D015544:Inositol 1,4,5-Trisphosphate; D011972:Receptor, Insulin; D002118:Calcium
Cancer Cell. 2004 Sep;6(3):251-61
15380516
EMBO J. 1997 Dec 1;16(23):7166-73
9384593
Mol Cell Endocrinol. 1984 Jun;36(1-2):123-9
6378690
Proc Natl Acad Sci U S A. 1989 Sep;86(17):6640-4
2672001
Biochem Biophys Res Commun. 2003 Feb 7;301(2):267-74
12565854
J Mol Endocrinol. 2005 Feb;34(1):153-61
15691885
Neuron. 1997 Sep;19(3):723-33
9331361
Anal Biochem. 2003 Feb 15;313(2):234-45
12605860
J Cell Biol. 1996 Mar;132(6):1133-49
8601590
Nat Rev Mol Cell Biol. 2003 May;4(5):349-60
12728269
J Biol Chem. 2008 Feb 15;283(7):4344-51
18073207
J Biol Chem. 2007 Mar 30;282(13):10057-10067
17284437
Nature. 2001 Dec 13;414(6865):799-806
11742412
J Biol Chem. 2002 Jul 26;277(30):27517-27
11971908
EMBO J. 1991 Nov;10(11):3207-14
1655412
J Biol Chem. 1987 Mar 5;262(7):3362-8
3546306
Methods Enzymol. 1990;192:501-16
1963665
Nature. 1997 Jan 16;385(6613):260-5
9000075
J Cell Biol. 2001 Mar 19;152(6):1307-12
11257130
Science. 1997 Apr 4;276(5309):60-6
9082986
Gastroenterology. 1999 May;116(5):1176-83
10220510
Gastroenterology. 2007 Jul;133(1):256-67
17631147
Nat Rev Drug Discov. 2002 Oct;1(10):769-83
12360255
Biochemistry. 2004 Dec 21;43(50):15873-83
15595842
J Cell Biochem. 2006 Aug 15;98(6):1570-83
16552725
Nat Rev Mol Cell Biol. 2002 Sep;3(9):697-702
12209129
Biochemistry. 1988 Jan 12;27(1):375-9
2831959
J Biol Chem. 1989 Oct 15;264(29):17131-41
2793847
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2975-80
12606721
Biochem Biophys Res Commun. 2001 Mar 30;282(2):615-20
11401505
Nature. 1986 Feb 13-19;319(6054):600-2
3945348
Science. 1981 Feb 27;211(4485):947-9
7008195
Gastroenterology. 2003 Oct;125(4):1175-87
14517800
Am J Physiol. 1997 Jun;272(6 Pt 1):G1425-32
9227478
J Biol Chem. 2005 Dec 9;280(49):40892-900
16192275
Nat Med. 2005 May;11(5):567-71
15821749
Biochem J. 1997 Sep 1;326 ( Pt 2):491-5
9291123
Trends Cell Biol. 2002 Feb;12(2):65-71
11849969
Nature. 1999 Mar 4;398(6722):80-4
10078534
Cell. 1995 Feb 10;80(3):439-44
7859285
Science. 1990 Nov 16;250(4983):977-9
2237441
J Biol Chem. 1985 Feb 25;260(4):2011-4
2982801
Nat Cell Biol. 2001 Sep;3(9):802-8
11533659
Am J Physiol. 1994 Sep;267(3 Pt 1):G338-49
7943230
J Biol Chem. 2007 Apr 6;282(14):10432-40
17283074
Mol Cell Biol. 2001 May;21(9):2981-90
11287604
Exp Cell Res. 1975 Aug;94(1):70-8
243
Gastroenterology. 2002 Apr;122(4):1088-100
11910359
J Biol Chem. 1986 Jul 5;261(19):8589-92
3522574
Nat Cell Biol. 2003 May;5(5):440-6
12717445
J Biol Chem. 2002 May 31;277(22):20041-50
11923287
Invest Ophthalmol Vis Sci. 1999 Aug;40(9):2046-53
10440260
J Biol Chem. 2007 Jun 8;282(23):17061-8
17420246
Nature. 1985 May 9-15;315(6015):147-9
3838803
EMBO J. 1997 Jan 15;16(2):242-51
9029145
Gastroenterology. 2007 Nov;133(5):1592-602
17916355
Nature. 1990 Dec 20-27;348(6303):735-8
1701852
Science. 1987 Sep 18;237(4821):1452-8
2442814
Science. 1990 Nov 30;250(4985):1253-6
1700866
Endocr Rev. 1984 Spring;5(2):356-69
6376081