Hormones Epinephrine, Cortisol, and Growth Hormone Flashcards
Epinephrine Structure
An amino acid derivative hormone
Synthesized from tyrosine
Epinephrine t1/2 = 1min (less than glucagon)
Epinephrine Secretion
In response to LOW BLOOD SUGAR and STRESS (a psychological aspect)
from the adrenal medulla
Epinephrine Receptor (aka adrenergic receptors)
alpha type: alpha1, alpha2, coupled to phosphoinositol mechanism
beta type: beta1, beta2, coupled to cAMP production
- general mechanism: Gs-protein coupled receptor -> increase cAMP -> activates protein kinase -> phosphorylates the target proteins
*no ‘general rule’ as to whether phosphorylated forms are active or inactive
- focus on: beta-type adrenergic receptors of the muscle, liver, and adipose tissue which mediate changes in fuel metabolism
Target Tissues and Downstream Effects of Epinephrine - Muscle?
Epinephrine Promotes:
- glycogen breakdown; glycolysis (muscles need energy)
Epinephrine Inhibits:
- ** glucose uptake from blood ** (blood glucose reserved for brain use)
Target Tissues and Downstream Effects of Epinephrine - Liver?
Epinephrine Promotes:
- glycogen breakdown; gluconeogenesis (releases more glucose to blood)
Epinephrine Inhibits:
- glycogen synthesis; glycolysis
Target Tissues and Downstream Effects of Epinephrine - Adipose Tissue?
Epinephrine Promotes?
- Lipolysis (mobilizing fatty acid release to liver, other tissues)
Epinephrine Inhibits:
- TAG synthesis
Target Tissues and Downstream Effects of Epinephrine - Pancreas?
Epinephrine Promotes:
- glucagon secretion (augments liver and adipose responses)
Epinephrine Inhibits:
- insulin secretion (via alpha-adrenergic receptors)
Epinephrine In General
Associated with LOW BLOOD SUGAR and STRESS
acts to INCREASE blood sugar and muscle activity
Cortisol Structure
Steroid hormone: specifically, glucocorticoid hormone
Synthesized from cholesterol in the mitochondrial matrix
- two important control points in cortisol synthesis: 1) movement of cholesterol from cytoplasm into mitochondria mediated by StAR (steroidogenic acute regulatory protein); 2) shortening the hydrocarbon chain of cholesterol (27C) to form pregnenolone (21C) - the parent compound for all steroid hormones. This step is catalyzed by desmolase (CYP11A or P450scc).
- Note: the zona fasciculata and zona reticularis of the adrenal cortex do not have the enzyme required for aldosterone (mineralocorticoids) synthesis (CYP11B2), which is secreted by the zona glomerulosa region of the adrenal cortex. The zona glomerulosa does not have a 17-alpha-hydroxylase (CYP17), thus cannot synthesize the glucocorticoids or androgens
Cortisol t1/2 = ~65mins (plasma clearance rate at normal hormone levels)
ACTH Stimulates Cortisol Synthesis and Secretion - Pathway?
Cortisol Secretion
Secreted in response to various stress factors (i.e. low blood glucose, starvation, anxiety, fear, pain, hemorrhage, infections)
Certain stress factors induce hypothalamic production and secretion of corticotrophin-releasing hormone (CRH)
CRH induces producjtion and secretion of adrenocorticotropic hormone (ACTH) by the anterior lobe of the pituitary
ACTH stiulates the adrenal cortex (in the zona fasciculata and zona reticularis) to synthesize and secrete cortisol
Cortisol Transport
Problem: cortisol is hydrophobic
Solution: transport cortisol (and other steroid hormones) attached to water-soluble carrier proteins in the plasma
- corticosteroid-binding globulin, CBG (aka transcortin): primary transporter of cortisol in the blood
- plasma albumin can act as a non-specific carrier of steroid hormones as well
Cortisol Receptors
- Receptors for steroid hormones are found within target cells
- recall: hydrophobic ligands can pass through membranes
- steroid receptor proteins have 3 domains: hormone-binding domain (HBD), DNA-binding domain (DBD), transcriptional regulatory domain (TRD) - Cortisol molecules pass through the cell membrane and bind to cytoplasmic glucocorticoid receptors (GR) at the HBD undergoing conformational changes
- The cortisols + glucocorticoid receptors dimerize and the whole receptor-ligand complex translocates into the cell nucleus to act as a transcription factor
- The DBD of the complex binds to the glucocorticoid responsive elements (GRE)
- GREs are specific DNA sequences recognized by these complexes
- each gene that responds to cortisol is under the control if its own GRE element; the GRE can be located upstream or downstream, and can function at great distances from the actual gene(s) - The TRD then recruits other co-activator proteins and the basal transcription complex - thus allowing for coordinated expression of a group of target genes that must respond to the presence of cortisol in the cell
- Example: cortisol results in the upregulation of the synthesis of phosphoenolpyruvate carboxykinase (PEPCK) - resulting in increased gluconeogenesis in the target cell (i.e. liver cells)
- Thus, cortisol exerts longer-term effects on energy metabolism by altering levels of various enzymes
Target Tissues and Downstream Effects of Cortisol - Liver?
Gluconeogenesis - STIMULATED or ‘permissive’
- permissive: implies that the hormone itself may not directly initiate certain processes; rather allows these processes to occur more efficiently when stimulated by other hormones
- recall, though, cortisol does increase synthesis of PEP carboxykinase (not the first enzyme of GNG, but a key enzyme in the pathway)
Glucose secretion to the blood - STIMULATED
Glycogen synthesis - STIMULATED (if glucose is not needed int he blood)
- prior exposure to normal [cortisol] allows for increased glycogen synthesis in liver, using aa supplied by proteolysis
- replenishes liver glycogen stores for effective mobilization by glucagon or epinephrine when needed
Target Tissues and Downstream Effects of Cortisol - Muscle?
Protein breakdown - STIMULATED
- occurs during fasting or when excess cortisol is present
- provides amino acids for the liver, which are the precursors for gluconeogenesis
Glucose uptake - INHIBITED (glucose reserved for brain)
Amino acid uptake - INHIBITED
Protein synthesis - INHIBITED
Target Tissues and Downstream Effects of Cortisol - Adipose Tissue?
Lipolysis - ‘permissive’
- weakly by cortisol itself; but not necessary for efficient stimulation of lipolysis by other hormones (i.e. epinephrine and growth hormone)
- glycerol released from lipolysis - another substrate for gluconeogenesis in the liver
Glucose uptake - INHIBITED (glucose reserved for brain)
Further Cortisol Effects
- Supports vascular responsiveness
- Modulates central nervous system functions
- Skeletal turnover
- Muscle function
- Immune responses
- Renal function
- Hematopoesis
Cortisol In General
CATABOLIC (i.e. anti-anabolic)
has anti-insulin effects
Growth Hormone (somatotropin) Structure
Globular 22kDa protein (polypeptide hormone)
Synthesized (RER) as pregrowth hormone (inactive
To Golgi as: progrowth hormone (inactive)
- a protease cleaves off amino-terminuse leader peptide
Stored and released from secretory granules as: growth hormone (active)
- a protease (in Golgi) cleaves off signal peptide from new amino-terminus
- active form = globular 191 aa single polypeptide chain w/ two intrachain disulfide bridges
Growth Hormone Secretion
In response to various stresses (i.e. fasting, hypoglycemia, sleep, exercise, stress)
from anterior pituitary
secretion mechanism: various stress factors induce hypothalamus to release growth hormone releasing hormone (GHRH), which stimulates the anterior pituitary to secrete GH
Decreased hypothalamic secretion of somatostatin can also lead to increased GH secretion
GH ‘direct’ and ‘indirect’ effects on target tissues
Direct effects = metabolic activities
Indirect anabolic effects of GH via IGF-I (insulin-like growth factor I):
- increased skeletal growth
- increased amino acid uptake and protein synthesis
- increased cell proliferation
Growth Hormone Receptor on Target Tissues
cells of many tissues and organs have GH receptors in their plasma membranes
binding of GH to its receptor acticvates JAK2 (Janus kinase 2) [an associated tyrosine kinase] -> JAK2 initiates changes in the phosphorylation pattern of many cytoplasmic and nuclear proteins
Results:
- ‘direct’ effects on many enzymatic activities of metabolic pathways
- ultimately stimulating transcription of specific genes, including IGF-I, which mediates the ‘indirect’ effects of GH
Target Tissues and Downstream ‘direct’ effects of growth hormone - Liver
Gluconeogenesis - STIMULATED
Ketone Body Synthesis - STIMULATED
Target Tissues and Downstream ‘direct’ effects of growth hormone - Adipose Tissue
Lipolysis - STIMULATED
Glucose Uptake - INHIBITED (glucose reserved for brain)
Target Tissues and Downstream ‘direct’ effects of growth hormone - muscle
Glucose Uptake - INHIBITED (glucose reserved for brain)
Target Tissues and Downstream ‘direct’ effects of growth hormone - NOTE
Anti-insulin (‘catabolic’) direct effects of growth hormone
GH does have ANABOLIC DIRECT EFFECTS: increased amino acid uptake and protein synthesis in muscle; and increased cell proliferation
Summarize the Effects of Insulin on Biochemical Actions
Increase cell permeability to glucose and amino acids
Increase glycolysis
Increase glycogen synthesis
Decrease gluconeogenesis
Increase Triacylglycerol synthesis
Decrease lipolysis (TAG breakdown)
Decrease protein degradation
Increase protein, DNA, and RNA synthesis
Summarize the Effects of Insulin on Physiological Actions
Signals FED STATE
Increase fuel storage
Decrease [blood glucose]
Increase cell growth and differentiation
Summarize the Effects of Glucagon on Biochemical Actions
Anti-Insulin Effect
Increase [cAMP] in liver and adipose tissue
Increase glycogenolysis
Decrease glycogen synthesis
Increase lipolysis (TAG breakdown)
Increase ketone body synthesis (liver)
Summarize the Effects of Glucagon on Physiological Actions
Increase glucose release from the liver
Increase [blood glucose]
Increase ketone body release from the liver
Summarize the Effects of Catecholamines (Epinephrine) on Biochemical Actions
Anti-Insulin Effect
Increase [cAMP] in muscle
Increase triacylglycerol mobilization
Increase glycogenolysis
Decrease glycogen synthesis
Summarize the Effects of Catecholamines (Epinephrine) on Physiological Actions
Increase glucose release from the liver
Increse [blood glucose]
Decrease glucose uptake by the muscle
Summarize the Effects of Growth Hormone on Biochemical Actions
Increase gluconeogenesis
Increase ketone body synthesis
Increase lipolysis (TAG breakdown)
Increase protein synthesis (muscle)
Summarize the Effects of Growth Hormone on Physiological Actions
Increase glucose release from the liver
increase [blood glucose]
Decrease glucose uptake by muscle and adipose tissue
Increase amino acid uptake (muscle)
Summarize the Effects of Glucocorticoids (Cortisol) on Biochemical Actions
Increase gluconeogenesis
Increase glycogen synthesis
Increase lipolysis (TAG breakdown)
Increase protein degradation
Decrease protein synthesis
Summarize the Effects of Glucocorticoids (Cortisol) on Physiological Actions
Increase glucose release from the liver
Increase [blood glucose]
Decrease glucose uptake by muscle and adipose tissue
Decrease amino acid uptake by muscle
What is important about the ratio of insulin:glucagon?
Because of the antagonistic effects of insulin and glucagon, the ratio is the critical factor (more so than the actual levels int he blood of each of these two hormones)
