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1st half of 1st lecture

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

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