Lecture 9 Flashcards
How do glucagon and insulin respond to blood glucose levels?
Insulin is released into blood from pancreatic beta cells when there is LOTS of glucose in the blood
Glucagon is released into blood from pancreatic alpha cells when there is LITTLE glucose in the blood.
What is glucagon?
A polypeptide hormone
Made in the alpha cells of the pancreas
Released from the pancreas when blood glucose levels are low (the mechanism that stimulates this release is similar, but not identical to the mechanism for insulin (not really known for sure yet))
Polypeptide is made as precursor, then cleaved into smaller peptides. One of these is glucagon
What is the pattern of daily fluctuations in plasma insulin levels?
Insulin increases after meals, and otherwise is at a stable low level
How do the glucagon levels match up with insulin levels throughout the day?
Glucagon typically at lower concentrations than insulin, but after meals when insulin is high it goes even lower (inverse relationship) and goes back up when insulin goes back down
What happens during endurance exercise over 4 hours?
Glucose levels fall. Glucagon levels increase and insulin levels decrease. Stimulation of breakdown fat and glycogen occurs. Stimulation of gluconeogenesis to make glucose occurs.
How does insulin work?
Insulin works by binding to a dimer of a single transmembrane type of receptor. Has an alpha subunit and a beta subunit. Binds to alpha subunit, and beta conformation changes. Beta subunit gets phosphorylated, leading to a cascade of kinases, which eventually activates Phosphatase-1. Phosphatase-1 removes phosphates (one of the many results of insulin binding).
What are epinephrine and glucagon?
Epinephrine is a small molecule derived from the amino acid tyrosine (a catecholamine). Glucagon is derived from a polypeptide chain. Both bind G-protein coupled receptors (7 transmembrane helices).
What happens when hormones like epinephrine or glucagon bind to G-protein coupled receptors?
Adenylyl cyclase is activated. (see flowchart)
How is the response to a hormone terminated?
The GTP bound to the G protein is hydrolyzed to GDP (has a timer, which inactivates the G protein). Either the hormone dissociates from the receptor, or the receptor (the carboxyl tail) becomes phosphorylated and this inactivates the G protein. Arrestin binds to the receptor to “cap” it (prevents G-protein from getting access).
Ligands interact and sometimes bind, sometimes do not. Dissociation results in the system turning off.
Cyclic AMP pathway and how it relates to caffeine?
ATP is converted by adenylate cyclase (AC) to 3’-5’ cyclic AMP “cAMP”. The driving force for this reaction is the additional product, a pyrophosphate. This turns into two phosphate groups (hydrolysis of pyrophosphate into 2 inorganic phosphates). Phosphodiesterase (PDE) converts 3’-5’ cyclic AMP to 5’ AMP.
PDE is inhibited by caffeine. This means that caffeine increases cAMP levels a little.
How is cyclic AMP-dependent Protein Kinase (PKA) regulated?
Initially an inactive holoenzyme (R2C2). Two R subunits, each with two cAMP binding domains. Psuedosubstrate sequence binds each R subunit to a C subunit, right at the active site (inactive as holoenzyme because active site is blocked). (R = regulatory subunit (inhibits C)) (C=catalytic subunit). It is activated by cAMP. 4 cAMPs bind (one in each binding domain). A conformational change occurs where the two regulatory sites dissociate from the catalytic subunits, and the active site is now accessible
It uses ATP to phosphorylate certain molecules.
How is glycogen phosphorylase regulated by phosphorylation?
Two conformations: phosphorylase b and phosphorylase a. Phosphorylase a is phosphorylated, phosphorylase b is not. Each can flicker through relaxed state or tense state. When not phosphorylated (b), flickering favors tense state. When phosphorylated (a), flickering favors relaxed state. The T state is less active than the R state because the active site is buried. Contains phosphoserine residues.
When active: capable of phosphorylating (get better breakdown, etc.).
What are two glycogen storage diseases (GSDs)?
Two phosphorylase genes, two phosphorylase deficiencies:
Type V: McCardle’s Disease
Type VI: Hers’ Disease
Type V: McCardle’s Disease
One of the glycogen storage diseases. It is a muscle glycogen phosphorylase deficiency. Results in exercise intolerance, muscle pain, fatigue, and cramps. Associated with nearly 100 mutations in the muscle phosphorylase gene.
Type VI: Hers’ Disease
One of the glycogen storage diseases. Liver glycogen phosphorylase deficiency. Symptoms are enlarged liver, hypoglycemia, elevated ketone bodies. Associated with greater than 17 mutations in the liver phosphorylase gene. You store a lot of glycogen, and get low levels of glucose. You get elevated ketone bodies because your body thinks you are starving.
