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50 terms

Endocrinology Lecture 1.1

1st half of 1st lecture
STUDY
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Endocrine
Cell to cell communication over a distance, usually through the blood
Paracrine
cell to cell communication between cells in close proximity
Autocrine
cell to cell communication with oneself
Hormone Types
Cellular tool for conveying a message.
1. Peptide
2. Amino Acid
3. Steroid
Target Cell
Cell type targeted by a hormone. Must contain or express receptor for hormone
Receptor
Contained either intracellularly (for steroid) or extracellularly (on the membrane). Must be present to receive the message from the hormone
Peptide Hormone
Protein coded by a gene. Usually made as a pre-pro hormone and modified to active form
Amino Acid Hormone
Made of modified amino acids via enzymes, such as tryptophan to dopamine
Steroid Hormone
Can act intracellularly. Lipophillic and able to diffuse into cell. All are derived from cholesterol, like cortisol, aldosterone, etc
Binding Proteins
Form complex with some hormones.
Allow for generation of a reserve stock of hormone and increases the half-life.
Protects from proteases by covering enzyme cut sites.
Bigger when in complex = harder to excrete.
Protein-bound hormones
Generally have chronic effects
Unbound hormones
Generally have acute effects. Important for things you want to increase or decrease very quickly.
Metabolic clearance rate
Volume of plasma cleared of the hormone per unit time.
Inversely related to Half-life.
Actions of/on secreted hormones
1. Bind a receptor and elicit a response
2. Be metabolically transformed by the liver
3. Undergo urinary excretion
Half-life
Time it takes for the hormone concentration to decrease by 50%.
Inversely related to metabolic clearance rate.
Affected by hormone size, glycosylation, binding proteins
Endocrine disorders result from:
1. Hormone concentration alterations
2. Changes in target cell responsiveness
Radioimmunoassay
Use of radio-labelled hormone and antibodies to determine hormone concentration. This is done by comparing the amount of radioactivity lost after addition of the sample (which is non-tagged)
Saturation Plot for RIA
Determines exactly how much radioactive hormone you need to saturate a set amount of antibody.
Displacement curve for RIA
Generation of a standard curve by adding known amounts of unlabelled hormone and measuring the decrease in radioactivity.
Determination of hormone concentration (RIA)
Add sample to saturated sample. Measure decrease in saturation, and determine concentration based on your standard curve.
Hypothalamic-Pituitary axis
Hypothalamus produces releasing hormone.
Releasing hormone causes Pituitary to produce/release a pituitary hormone
Pituitary hormone acts on target organ or tissue
*Negative feedback inhibits various steps
Long-loop feedback
Target organ (etc) acts on organs 2 or more steps away to the pathway, like target organ causing negative feedback on the hypothalamus, such as cortisol
Short-loop feedback
Feedback that acts one step back, like the pituitary inhibiting the hypothalamus. ACTH is an example
Ultrashort-loop feedback
Feedback on self, like oxytocin positive feedback
Regulation of Hypothalamic-Pituitary axis
Neural
Hormonal
Nutrient
Peptide Hormone expression
Constitutive- Constant vesicle release
Regulated- only under certain conditions. Stored.
Constitutive Peptide Hormone
Made and secreted. No storage. Regulation is at level of DNA rather than level of secretion
Regulated Peptide Hormone
Make peptide, send to Golgi to process, package into secretory vesicles, stored until needed
Ligand Binding Domain
Binds hormone.... the listener
1. Cell surface receptors (peptide and AA)
2. Intracellular receptors (steroid and thyroid)
Effector Domain
Causes the effect.... the talker
Peptide hormone receptors
Are cell surface receptors
1. G-protein coupled receptors (GPCR)
2. Receptor Tyrosine Kinase
3. Tyrosine Kinase-Associated Receptors
Amino Acid Hormone Receptors
Adrenoreceptors, Dopamin receptors, etc... classic GPCRs that are cell surface receptors EXCEPT thyroid hormones = intracellular
Steroid hormones (and thyroid) receptors
intracellular
Specificity
The ability of a receptor to discriminate between hormones
G-Protein Coupled Receptors
GαS
GαI
GαQ
GαS
The most common and activates Adenylyl cyclase to increase cAMP and increase protein kinase A
Kinase
Enzyme that phosphorylates proteins. Can have a fast response if phosphorylates another enzyme, slow if phosphorylates a transcription factor
GαI
inhibits adenylyl cyclase, so decreases cAMP and PKA, so decreases the kinase activity
GαQ
interacts with and activates Phospholipase C.
Increases Diacylglycerol (DAG), and protein kinase C (PKC) = phosphorylation.... increases [Ca²⁺] too, from endoplasmic reticulum and extracellular
Hormones that activate adenylyl cyclase pathway
GαS!!!
Corticotropin-releasing hormone (CRH)
Growth Hormone-Releasing Hormone (GHRH)
Adrenocorticotropic Hormone (ACTH)
Thyroid Stimulating Hormone (TSH)
Glucagon
Epinephrine
Dopamine
Parathyroid Hormone (PTH)
Hormones that inhibit the adenylyl cyclase pathway
GαI
Somatostatin (SS)
Norepinephrine (NE)
Dopamine (DA)
GPCR/PLC Pathway activators
GαQ!!!
Thyroptropin-releasing hormone (TRH)
Calcium
Oxytocin
Norepinephrine (NE)
Parathyroid Hormone (PTH)
Hormones that bind receptor tyrosine kinases
Insulin
IGF-I
IGF-II
Each receptor has a kinase domain, which results in a conformational change that allows the signal to be passed from outside to inside
Hormones that bind tyrosine kinase-associated receptors
Kinase not part of the receptor....associated.
Hormone binds to extracellular domain, which causes change that activates associated kinase.
Growth Hormone (GH)
Prolactin
Intracellular receptors
Slow effect, only
Directly regulate only gene transcription
Steroids (like aldosterone, cortisol, vitamin D)
Thyroid Hormones (T₃, T₄)
Affinity
How strongly/tightly a hormone is bound by the receptor (Ka = association constant = [HR]/[H][R])
Low Ka = low binding
High Ka = high binding affinity
Kd
dissociation constant
= [H][R]/[HR]
Low = high binding
High = low binding
Receptor Binding Assay
Measures receptor affinity and concentration. Extracts with unknown amount of hormone mixed with known amounts of radio-labelled hormone. Saturation curve.
Nonlinear Regression for RBA
Most accurate
Computer based, using the saturation curve
Scratchard Plot for RBA
More visual... old way... and way of seeing saturation. Takes [HR]/[H] on Y axis and [HR] on X axis to get slope that equals -1/Kd