Compartmental Models for Regulated Exocytosis
Arthur Sherman
Laboratory of Biological Modeling National Institute of Diabetes & Digestive & Kidney Diseases
NIH
Compartmental Models for Regulated Exocytosis
Arthur Sherman
Laboratory of Biological Modeling National Institute of Diabetes & Digestive & Kidney Diseases
NIH
Outline
Theme: Progressive Reductionism in the Models
Grodsky: Two Pools
Bertuzzi: Distinguishing metabolism and calcium
Chen, Wang, Sherman:
Add single cells (faster time scales)
Calcium compartments (smaller space scales)
Pedersen, Sherman: Newcomers (Nagematsu) and HCSP (Yang and Gillis)
Opportunities for REx
Outline
Grodsky: Two Pools
Bertuzzi: Distinguishing metabolism and calcium
Chen, Wang, Sherman:
Add single cells (faster time scales)
Calcium compartments (smaller space scales)
Pedersen, Sherman: Newcomers (Nagematsu) and HCSP (Yang and Gillis)
Opportunities for REx
Basic Two-Pool Model for Exocytosis
First phase due to release of labile pool
Second phase due to re-supply of labile pool Glucose 10000 600
Simulation of Perfused Rat Pancreas
Grodsky, JCI 51:2047 1972
Response to a glucose step
First phase: rapid (10 min)
Second phase: maintained or rising (1 hr)
Potentiation when re-add glucose due to build-up of labile pool
No First Phase When Glucose is Ramped
Grodsky, JCI 51:2047 1972 Secretion depends on history
Second phase: “Integral control” (how long)
First phase: “Derivative control” (how fast)
Outline
Grodsky: Two Pools
Bertuzzi: Distinguishing metabolism and calcium
Chen, Wang, Sherman:
Add single cells (faster time scales)
Calcium compartments (smaller space scales)
Pedersen, Sherman: Newcomers (Nagematsu) and HCSP (Yang and Gillis)
Opportunities for REx
Calcium Sufficient for 1st Phase, Glucose Necessary for 2nd Phase
Straub et al. Am J Physiol Cell Physiol 287: C565-C571 2004 Hypothesis:
There is a
Metabolic
Amplifying
Factor Sulfonylureas only raise Ca2+:
unbalanced therapy
Bertuzzi Model Shows 1st Phase, 2nd Phase, Potentiation, Ramp
Bertuzzi et al, AJP Endo Metab 293:E396 2007
Outline
Grodsky: Two Pools
Bertuzzi: Distinguishing metabolism and calcium
Chen, Wang, Sherman:
Add single cells (faster time scales)
Calcium compartments (smaller space scales)
Pedersen, Sherman: Newcomers (Nagematsu) and HCSP (Yang and Gillis)
Opportunities for REx
Fusion from Isolated Cell by Capacitance
Barg et al, Neuron 33:287 2002 C (fusion) TIRF (release)
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