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Glucagon What: 29 amino acid peptide Where: a cells of pancreas When: low blood glucose in response to adrenalin (stress) Glucagon receptor What: 7 transmembrane, G protein coupled Where: liver, adipocytes, and elsewhere (brain, pancreas a cells) Effect: increased production of cAMP liver: increased glyogenolysis and gluconeogenesis adipocytes: increased lipolysis Glucagon receptor (Gs) Liver cAMP I-1 PKA PP1 Phos GS PP1 PFK2 Phosphorylase kinase Glycogen synthase F 2,6 bisP FBPase PK Phosphorylase Glycogenolysis Glucose export Glycolysis Gluconeogenesis Epinephrine/Adrenalin HO HO H C C H2 N R H2 OH Epinephrine: R = CH3 Nor-epinephrine: R = H Where: adrenal medula When: stress – release of AcCholine by neurons stimulates chromaffin cells of adrenal medula to release adrenalin Receptors: a liver b liver and muscle (cAMP) Effect: liver increased glycogenolysis, gluconeogenesis muscle inclreased glycogenolysis, glycolysis Adrenalin: a1-receptor (Gq) liver Ca2+ Phosphorylase kinase Insulin receptor PKC Glycogen synthase Glycogenesis Phosphorylase HO HO Glycogenolysis H C C H2 N R H2 OH Epinephrine: R = CH3 Nor-epinephrine: R = H Adrenalin: b-receptor (Gs) cAMP Muscle I-1 PP1 PKA GS PP1 FBPase Phosphorylase kinase Glycogen synthase Phos F 2,6 bisP Heart muscle Glycolysis Phosphorylase Glycogenolysis Note: muscle isoform of PK is not phosphorylated by PKA Insulin What: dimeric polypeptide 21 and 31 amino acids linked by S-S Where: b cells of pancreas (note: b cells contain GluT2) When: post absorptive state Insulin receptor What: tetrameric (2a, 2b), transmembrane tyrosine kinase Where: liver, muscle, adipocytes Effect: muscle – translocation of GluT4 increased glycogenesis liver: increased glycogenesis, increased glycolysis See figures 9-45 and 9-46 Horton Insulin Liver IRTK Several steps Phos Several steps ISPK Phosphatase GS PK Glycogen synthase kinase PFK2 F 2,6 bisP PDH Glycogen synthase Glycogenesis Glycolysis AcCoA (for biosynthetic purposes Insulin Muscle IRTK Several steps Phos Several steps ISPK Phosphatase Translocation of GluT4 Glucose uptake GS Glycogenesis G6P Summary of regulation of carbohydrate metabolism 1. Regulation by energy charge or metabolic intermediates • Hexokinase G6P • Glucokinase F6P (with regulatory protein) • PFK1 ATP, citrate; AMP, F2,6 bisP • PK ATP, F1,6 bisP • PDH AcCoA, NADH • F-1,6 bis Pase citrate, AMP, F2,6,bisP • Pyruvate carboxylase AcCoA • Isocitrate dehydrogenase NADH • Phosphorylase b AMP (muscle), G6P, ATP • Glycogen synthase b G6P 2. Regulation by phosphorylation • PFK2: inhibited in liver, activated in heart muscle • F-2,6-bis Pase: activated in liver • Pyruvate kinase: inhibited • Pyruvate dehydrogenase: inhibited (liver, PDH kinase and PDH phosphatase) • Phosphorylase activated by phosphorylase kinase • Glycogen synthase inhibited PKA and glycogen synthase kinase 3. Regulation by calcium - muscle • PDH phosphatase activated • Phosphoryae kinase activated • Isocitrate dehydrogenase activated • a-ketoglutarate dehydrogenase activated 4. Glucose “sensors” • GluT 2 liver, pancreas • Glucokinase liver • Phosphorylase a/PP1
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