Abstract

This application explores stimulation-secretion coupling in the beta islet cells of the pancreas. The investigator has hypothesized that a subpopulation of insulin granules are 'loosely co-localized' with Ca2+ channels in the plasmalemma, and these granules are released rapidly in response to local increases in Ca2+ concentration.
The specific aims test four predictions of this co-localization model: 1) release should have a distinctive relationship to total Ca2+ entry that should be independent of the conditions initiating that entry; 2) widely-separated depolarizations should evoke insulin release with distinct latency periods; 3) sustained Ca2+ entry should deplete the co-localized pool of granules, resulting in a period of quiescence while that pool is replenished; and 4) conditions that increase the size of the co-localized pool should permit prolonged bouts of secretion. To evaluate these predictions, the investigator will use instrumentation capable of measuring these parameters of stimulation and secretion simultaneously in single beta cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037380-11
Application #
2838089
Study Section
Physiology Study Section (PHY)
Program Officer
Laughlin, Maren R
Project Start
1986-07-01
Project End
2000-11-30
Budget Start
1999-03-05
Budget End
1999-11-30
Support Year
11
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110

  Publications

Misler, Stanley; Gillis, Kevin D (2012) Modes of exocytosis and electrogenesis underlying canine biphasic insulin secretion. Front Biosci (Elite Ed) 4:669-76
Silva, Amelia M; Dickey, Adam S; Barnett, David W et al. (2009) Ion channels underlying stimulus-exocytosis coupling and its cell-to-cell heterogeneity in beta-cells of transplantable porcine islets of Langerhans. Channels (Austin) 3:91-100
Misler, Stanley; Zhou, Zhuan; Dickey, Adam S et al. (2009) Electrical activity and exocytotic correlates of biphasic insulin secretion from beta-cells of canine islets of Langerhans: contribution of tuning two modes of Ca2+ entry-dependent exocytosis to two modes of glucose-induced electrical activity. Channels (Austin) 3:181-93
Misler, Stanley (2009) Unifying concepts in stimulus-secretion coupling in endocrine cells and some implications for therapeutics. Adv Physiol Educ 33:175-86
Misler, Stanley; Silva, Amelia M; Barnett, David et al. (2009) Phasic and tonic modes of depolarization-exocytosis coupling in beta-cells of porcine islets of Langerhans. Channels (Austin) 3:101-9
Luciani, Dan S; Misler, Stanley; Polonsky, Kenneth S (2006) Ca2+ controls slow NAD(P)H oscillations in glucose-stimulated mouse pancreatic islets. J Physiol 572:379-92
Silva, Amelia M; Liu-Gentry, June; Dickey, Adam S et al. (2005) alpha-Latrotoxin increases spontaneous and depolarization-evoked exocytosis from pancreatic islet beta-cells. J Physiol 565:783-99
Misler, Stanley; Dickey, Adam; Barnett, David W (2005) Maintenance of stimulus-secretion coupling and single beta-cell function in cryopreserved-thawed human islets of Langerhans. Pflugers Arch 450:395-404
Johnson, James D; Ahmed, Noreen T; Luciani, Dan S et al. (2003) Increased islet apoptosis in Pdx1+/- mice. J Clin Invest 111:1147-60
Johnson, James D; Misler, Stanley (2002) Nicotinic acid-adenine dinucleotide phosphate-sensitive calcium stores initiate insulin signaling in human beta cells. Proc Natl Acad Sci U S A 99:14566-71

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