Flashcards in Lecture 59 Deck (27)
How can hormones be classified by mechanism of action?
Hormones can bind to:
1) Receptors with intrinsic enzymatic activity (e.g. insulin, epidermal growth factor (EGF), growth hormone (somatotropin, GH), TGF Beta superfamily (BMPs, activins, inhibins)
2) Receptors with associated enzymatic activity (e.g. cytokines such as erythropoietin (EPO), interferons, GMCSF, prolactin)
3) G-protein coupled receptors (GPCR)/7 transmembrane receptors (e.g. glucagon, ACTH, TSH, LH, FSH, calcitonin, parathyroid hormone (PTH), opioids and cannabinoids, prostaglandins, thrombin, dopamine & hundreds more if olfaction included)
4) Receptors that stimulate intracellular protein cleavage (e.g. Tumor necrosis factor (TNF) alpha, interleukin
What kind of enzyme activity do cytokine receptors have?
Associated, instead of intrinsic (like RTKs)
What are examples of cytokine receptors and their functions?
1) The small and similarly structured cytokines play essential roles in blood cell differentiation, e.g.
2) Erythropoietin increases erythrocyte production
3) Interferons increase virus resistance
4) GMCSF increases granulocyte & macrophage production
5) Interleukins control T & B cell differentiation
What does an associated enzyme do differently than an intrinsic enzyme?
Instead of increasing the intrinsic enzyme activity in the receptor, cytokine binding (for example) activates kinases associated with (bound to) the intracellular domain
What are the steps of erythropoietin inducing erythrocyte production?
1) If a hematopoietic stem cell does not encounter erythropoietin, it undergoes apoptosis (cell death)
2) If a hematopoietic stem cell encounter erythropoietin, erythropoietin will bind to Epo receptors on the hematopoietic stem cell
3) Ligand binding activates JAK kinase (associated protein)
4) STAT binds to phosphorylated JAK kinase to produce activated Phopho-STAT
5) Dimerization occurs to STAT protein (signal transducers & activators of transcription)
6) Activated phospho-STAT enters nucleus and induces transcription
What are receptors that lack any enzyme activity?
1) G-protein coupled receptors (GPCR)/7 transmembrane receptors
2) Receptors that stimulate intracellular protein cleavage
Once a hormone such as Glucagon, ACTH, or epinephrine activates a receptor, what occurs to the signal?
1) It becomes amplified within the cell
2) Example: Epinephrine activates Adenylyl cyclase, which activates cAMP, which activates Protein kinase A, which activates an enzyme, which produces a product (each step includes amplification)
How is a G-protein (GTP-Binding protein) activated?
1) Instead of being phosphorylated, G-proteins are activated when GTP is bound to them
2) Instead of being dephosphorylated, G-proteins are deactivated when GDP is bound to them
3) To switch between active and inactive forms, GDP can be released and replaced with a new GTP (would make the protein active)
What do major alpha G-proteins do once they are activated in path #1?
1) Lose Beta & gamma parts of protein once activated
2) Heterotrimers activate cAMP synthesis & protein kinase A (PKA)
3) This causes cytosolic & nuclear events to occur
What are a few roles of cAMP?
1) Activates varied transcription factors
2) Fuels metabolism
a. Epinephrine & glucagon increase cAMP causes
b. Glycogen & fat breakdown & halts
c. Glycogen synthesis
3) Mineral Metabolism
a. PTH increases cAMP promotes bone resorption & increases renal calcium uptake (reabsorption)
What do normal PTH, glucagon, calcitonin, GH releasing hormone, TSH, & gonadotropin signaling all do in the cytosol or nucleus?
Produce normal glycogen, fat, & mineral metabolism and partake in development
What do abnormal PTH, glucagon, calcitonin, GH releasing hormone, TSH, & gonadotropin signaling all do in the cytosol or nucleus?
2) PTH Resistance
5) Short stature
6) Sexual Immaturity
What are examples of hereditary diseases that may be caused by activating and inactivating mutations in the GNAS1 gene encoding the alpha G protein?
1) Albright hereditary osteodystrophy
2) Pseudohypoparathyroidism (PHP), Type 1A
3) McCune-Albright syndrome
4) Progressive Osseous heteroplasia
5) Polyostotic fibrous dysplasia of bone
6) Pituitary tumors
What are characteristics of Albright Hereditary Osteodystrophy (type of pseudohypoparathyroidism (PHP))?
1) Short stature
2) Round face
4) Subcutaneous ossification → Ectopic bone formation
How can one clinically test for a PHP?
Intravenous injection of PTH should normally cause levels of urinary excretion of cAMP (or phosphate) to spike, except for in pseudohypoparathyroidism (PHP)
What is a major difference between hypoparathyroidism & pseudohypoparathyroidism?
1) In contrast to hypoparathyroidism where circulating PTH is decreased leading to hypocalcemia & hyperphosphatemia, circulating PTH is increased in pseudohypoparathyroidism
2) However, the target tissue is unresponsive to elevated levels of PTH
In AHO, urinary excretion of cAMP is impaired in response to PTH administration. What is defective?
A trimeric G protein
What is the second Major G-protein activated path?
1) Acetylcholine, vasopressin, or thrombin (for examples) can activated a G-protein linked receptor
2) Activated alpha G protein subunit can activate phospholipase C
3) Activated phospholipase C can activated a membrane phospholipid which is released from a diacylglycerol (DAG) in the membrane
4) The phospholipid component released from DAG (Inositol 1,4,5-triphosphate (IP3) can open a Ca2+ channel in the ER
5) Calcium can then be released into the cytosol where is binds to protein kinase C (PKC) now bound to DAG to continue cellular events
What are a few roles of Ca2+?
1) Activates varied transcription factors
2) Ca2 stimulates muscle contraction & secretion of gastric enzymes, hormones & neurotransmitters (along with others)
What helps to further modulate the cell's response to hormones?
Crosstalk between paths (G-protein path 1 & 2)
How can G-protein pathways be reversed?
1) Phosphatases counteract kinases
2) 2nd messenger elevation if fleeting (e.g. constitutive cAMP phosphodiesterase activity & continuous pumping of Ca2+ out of cytoplasm
3) GTP hydrolysis by intrinsic GTPase activity inactivates G proteins
How is NF-kB activated?
1) Normally, I-kappaBalpha is bound to NF-B, rendering it inactive (inhibitor)
2) When Tumor Necrosis Factor (TNF) alpha or Interleukin1 (IL-1) is activated, they cause kinase activation whihc phosphorylates I-kappaBalpha
3) Phosphorylated I-kappaBalpha is tagged by ubiquitin for proteasome cleavage, allowing NF-kB to be unbound and free to function
4) This is an example of irreversible receptor activation
What other function does Tumor Necrosis Factor (TNF) alpha have other than activating NF-kB?
Death inducing signaling complex (DISC) --> Caspase protease cascade --> Cell Death/Apoptosis
What are other important receptors that cause protein cleavage other than TNF alpha or IL-1?
1) Wnt receptors (colon cancer, etc.)
2) Hedgehog receptors (basal cell carcinoma, etc.)
3) Notch receptors (T-cell acute lymphoblastic leukemia, calcific aortic valve disease, etc.)
What is the most fundamental
difference between RTK or G-
protein coupled receptors and
receptors that cause protein
Unlike kinase and G-protein pathways, protein cleavage is not a “switch”. Protein cleavage is irreversible.
How are pathways stopped (how are hormone effects reversed)?
1) Rapid removal of 2nd messengers (e.g. constitutive cAMP phosphodiesterase activity and continuous pumping of Ca2+ out of cytoplasm)
2) Phosphatases counteract kinases
3) GTP hydrolysis by intrinsic GTPase activity