Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model
Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model Patrick P.L. Lam 1 2 , Yuk-Man Leung 1 2 , Laura Sheu 1 2 , James Ellis 3 , Robert G. Tsushima 1 2 , Lucy R. Osborne 1 4 and Herbert Y. Gaisano 1 2 1 Department of Medicine, University of Toronto, Toronto, Canada 2 Department of Physiol...
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| Published in | Diabetes (New York, N.Y.) Vol. 54; no. 9; pp. 2744 - 2754 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Alexandria, VA
American Diabetes Association
01.09.2005
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0012-1797 1939-327X |
| DOI | 10.2337/diabetes.54.9.2744 |
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| Abstract | Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model
Patrick P.L. Lam 1 2 ,
Yuk-Man Leung 1 2 ,
Laura Sheu 1 2 ,
James Ellis 3 ,
Robert G. Tsushima 1 2 ,
Lucy R. Osborne 1 4 and
Herbert Y. Gaisano 1 2
1 Department of Medicine, University of Toronto, Toronto, Canada
2 Department of Physiology, University of Toronto, Toronto, Canada
3 Program in Developmental Biology, Sick Kids Hospital, Toronto, Canada
4 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada
Address correspondence and reprint requests to Herbert Y. Gaisano, MD, University of Toronto, Room 7226, Medical Science Building,
1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: herbert.gaisano{at}utoronto.ca . Or Lucy R. Osborne, PhD, University of Toronto, Room 7238, Medical Science Building, 1 King’s College Circle, Toronto, Ontario,
Canada M5S 1A8. E-mail: lucy.osborne{at}utoronto.ca
Abstract
Soluble N -ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only
in exocytosis, but also binds and regulates Ca 2+ and K + (voltage-gated K + and ATP-sensitive K + channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are
reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose
homeostasis. We investigated the specific role of STX-1A in pancreatic β-cells by generating transgenic mice, which express
a moderately increased level (∼30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice
displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance
test, with correspondingly reduced plasma insulin levels. Surprisingly, β-cells from the STX-1A male mice also exhibited abnormal
insulin tolerance. To unequivocally determine the β-cell secretory defects, we used single-cell analyses of exocytosis by
patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases
were reduced in the STX-1A mouse islet β-cells. The STX-1A mouse also exhibited reduced currents through the Ca 2+ channels but little change in the voltage-gated K + channel or ATP-sensitive K + channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential
regulation of β-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.
Cm, membrane capacitance
GST, glutathione S-transferase
IPGTT, intraperitoneal glucose tolerance test
KATP channel, ATP-sensitive K+ channel
Kv channel, voltage-gated potassium channel
NSF, N-ethylmaleimide–sensitive factor
SNAP-25, synaptosome-associated protein of 25 kDa
SNARE, soluble NSF attachment protein receptor
STX-1A, syntaxin-1A
TEA, tetraethylammonium
VAMP-2, vesicle-associated membrane protein 2
WBS, Williams-Beuren syndrome
Footnotes
P.P.L.L. and Y.-M.L. contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 7, 2005.
Received November 23, 2004.
DIABETES |
|---|---|
| AbstractList | Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca(2+) and K(+) (voltage-gated K(+) and ATP-sensitive K(+) channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic beta-cells by generating transgenic mice, which express a moderately increased level ( approximately 30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, beta-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet beta-cells. The STX-1A mouse also exhibited reduced currents through the Ca(2+) channels but little change in the voltage-gated K(+) channel or ATP-sensitive K(+) channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of beta-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion.Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca(2+) and K(+) (voltage-gated K(+) and ATP-sensitive K(+) channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic beta-cells by generating transgenic mice, which express a moderately increased level ( approximately 30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, beta-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet beta-cells. The STX-1A mouse also exhibited reduced currents through the Ca(2+) channels but little change in the voltage-gated K(+) channel or ATP-sensitive K(+) channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of beta-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. Soluble N-ethylmaleimide--sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates [Ca.sup.2+] and [K.sup.+] (voltage-gated [K.sup.+] and ATP-sensitive [K.sup.+] channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic β-cells by generating transgenic mice, which express a moderately increased level (~30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, β-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the β-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet β-cells. The STX-1A mouse also exhibited reduced currents through the [Ca.sup.2+] channels but little change in the voltage-gated [K.sup.+] channel or ATP-sensitive [K.sup.+] channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of β-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model Patrick P.L. Lam 1 2 , Yuk-Man Leung 1 2 , Laura Sheu 1 2 , James Ellis 3 , Robert G. Tsushima 1 2 , Lucy R. Osborne 1 4 and Herbert Y. Gaisano 1 2 1 Department of Medicine, University of Toronto, Toronto, Canada 2 Department of Physiology, University of Toronto, Toronto, Canada 3 Program in Developmental Biology, Sick Kids Hospital, Toronto, Canada 4 Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada Address correspondence and reprint requests to Herbert Y. Gaisano, MD, University of Toronto, Room 7226, Medical Science Building, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: herbert.gaisano{at}utoronto.ca . Or Lucy R. Osborne, PhD, University of Toronto, Room 7238, Medical Science Building, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: lucy.osborne{at}utoronto.ca Abstract Soluble N -ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca 2+ and K + (voltage-gated K + and ATP-sensitive K + channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic β-cells by generating transgenic mice, which express a moderately increased level (∼30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, β-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the β-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet β-cells. The STX-1A mouse also exhibited reduced currents through the Ca 2+ channels but little change in the voltage-gated K + channel or ATP-sensitive K + channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of β-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. Cm, membrane capacitance GST, glutathione S-transferase IPGTT, intraperitoneal glucose tolerance test KATP channel, ATP-sensitive K+ channel Kv channel, voltage-gated potassium channel NSF, N-ethylmaleimide–sensitive factor SNAP-25, synaptosome-associated protein of 25 kDa SNARE, soluble NSF attachment protein receptor STX-1A, syntaxin-1A TEA, tetraethylammonium VAMP-2, vesicle-associated membrane protein 2 WBS, Williams-Beuren syndrome Footnotes P.P.L.L. and Y.-M.L. contributed equally to this work. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 7, 2005. Received November 23, 2004. DIABETES Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca(2+) and K(+) (voltage-gated K(+) and ATP-sensitive K(+) channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic beta-cells by generating transgenic mice, which express a moderately increased level ( approximately 30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, beta-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet beta-cells. The STX-1A mouse also exhibited reduced currents through the Ca(2+) channels but little change in the voltage-gated K(+) channel or ATP-sensitive K(+) channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of beta-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. Soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca2+ and K+ (voltage-gated K+ and ATP-sensitive K+ channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic β-cells by generating transgenic mice, which express a moderately increased level (∼30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, β-cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the β-cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet β-cells. The STX-1A mouse also exhibited reduced currents through the Ca2+ channels but little change in the voltage-gated K+ channel or ATP-sensitive K+ channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of β-cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also binds and regulates Ca super(2+) and K super(+) (voltage-gated K super(+) and ATP-sensitive K super(+) channels) to influence the sequence of events leading to secretion. Islet levels of STX-1A and cognate SNARE proteins are reduced in type 2 diabetic rodents, suggesting their role in dysregulated insulin secretion contributing to the abnormal glucose homeostasis. We investigated the specific role of STX-1A in pancreatic beta -cells by generating transgenic mice, which express a moderately increased level ( similar to 30% higher) of STX-1A in pancreatic islets (hereafter called STX-1A mice). The STX-1A mice displayed fasting hyperglycemia and a more sustained elevation of plasma glucose levels after an intraperitoneal glucose tolerance test, with correspondingly reduced plasma insulin levels. Surprisingly, beta -cells from the STX-1A male mice also exhibited abnormal insulin tolerance. To unequivocally determine the beta -cell secretory defects, we used single-cell analyses of exocytosis by patch clamp membrane capacitance measurements and ion channel recordings. Depolarization-evoked membrane capacitance increases were reduced in the STX-1A mouse islet beta -cells. The STX-1A mouse also exhibited reduced currents through the Ca super(2+) channels but little change in the voltage-gated K super(+) channel or ATP-sensitive K super(+) channel. These results suggest that fluctuation of islet STX-1A levels in diabetes could influence the pathological and differential regulation of beta -cell ion channels and the exocytotic machinery, collectively contributing to the impaired insulin secretion. |
| Audience | Professional |
| Author | Lucy R. Osborne James Ellis Patrick P.L. Lam Robert G. Tsushima Yuk-Man Leung Laura Sheu Herbert Y. Gaisano |
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| Keywords | Endocrinopathy Syntaxin Vertebrata Mammalia Mouse Diabetes mellitus Rodentia Transgenic animal Models |
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| Snippet | Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model
Patrick P.L. Lam 1 2 ,
Yuk-Man Leung 1 2 ,
Laura Sheu 1 2 ,
James Ellis 3 ,
Robert G. Tsushima... Soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also... Soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also... Soluble N-ethylmaleimide--sensitive factor (NSF) attachment protein receptor (SNARE) protein syntaxin-1A (STX-1A) plays a role not only in exocytosis, but also... |
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| SubjectTerms | Animals Biological and medical sciences Calcium Channels - physiology Diabetes Diabetes mellitus Diabetes Mellitus - genetics Diabetes Mellitus - physiopathology Diabetes research Diabetes. Impaired glucose tolerance Disease Models, Animal Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Exocytosis - physiology Female Gene Expression - physiology Genetic aspects Glucose Glucose Tolerance Test Homeostasis Insulin Insulin - metabolism Insulin Resistance - genetics Insulin Resistance - physiology Islands of Langerhans Islets of Langerhans Islets of Langerhans - metabolism Male Medical sciences Metabolism Mice Mice, Transgenic Observations Potassium Channels - physiology Proteins Transgenic animals |
| Title | Transgenic Mouse Overexpressing Syntaxin-1A as a Diabetes Model |
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