Principles of Endocrinology Flashcards
Hormone
Chemical secreted in trace amounts by one or more cells (and carried in the bloodstream to another cell) where it modulates a specific biochemical or physiological response
What is the difference between endocrine and exocrine?
- Endocrine: through blood
- Exocrine: through duct
Gland
Organ which can secrete a particular chemical substance for use within the body or into the surroundings (single gland may secrete multiple hormones but not all glands secrete hormones) (ex: salivary gland)
Endocrine signaling
Uses circulating system to transport ligand to target cells
Paracrine Signaling
Ligand acts on nearby cells (ex: synapse (neurocrine))
Autocrine Signaling
Ligand acts on secreting cell
Tropic Hormone
Hormone that targets another endocrine tissue
Protein and Peptide Hormones
- Few amino acids or hundreds
- Linear, ring structure or dimers
- Transcription and translation
- One gene can produce different proteins (alternative splicing)
- Post-translational regulation can also lead to several products
- Ex: Proopiomelanocortin (POMC): mutation impacts metabolism and stress
Peptide Hormone Production
- Transcription (Nucleus)
- Translation (ER: ribosomes)
- Processing (ER -> vesicles -> Golgi)
- Packaging (Golgi -> secretory vesicles -> secretion)
- Preprohormone (ER) -> Prohormone (vesicle) -> hormone -> degraded or reuptake
Regulated Secretion
- Peptide hormones
- cell stores hormone in secretory granules and releases them in bursts when stimulated
- Most common
Constitutive Secretion
- Peptide hormones
- Cell does not store hormone, but secretes it from secretory vesicles as it is synthesized
Neurotransmitters
- Enzymatically modified amino acids
- Synthesized by neurons and released into the synaptic cleft
Neurochemically Active Amino Acids
- Fast excitatory/inhibitory transmission
- Glutamate (+): exhibitory
- GABA (-): inhibitory
Monoamines
- One amino acid connected to aromatic ring
- Modulation of network activity (slower)
- ex: Catecholamines: Dopamine (DA), Norepinephrine (NE, NA), Epinephrine, Serotonin
Peptides (Neuromodulator Peptides)
- Slower modulation of circuit function
- ex: Cannabinoid, oxytocin, orexin, CART
Acetylcholine
Synthesized via enzymatic modification of precursors acetyl-CoA and choline
Steroid Hormone Synthesis
- Synthesis stimulated by tropic peptide hormones
- Mainly produced in adrenal cortex and gonads
Cholesterol
Precursor for all steroid hormones and vitamin D3 and steroid hormone metabolites and bile acids
Explain the two types of corticosteroids produced in the adrenal cortex.
- Glucocorticoids: glucose + cortex + steroid; role in glucose metabolism, immune/stress response
- Cortisol, corticosterone, cortisone - Mineralocorticoids: regulates electrolytes and fluid balance (aldosterone)
What type of corticosteroids are produced in the zona glomerulosa of the adrenal cortex?
Mineralocorticoids
What type of corticosteroids are produced in the zona fasiculata of the adrenal cortex?
Glucocorticoids
What type of corticosteroids are produced in the zona reticularis of the adrenal cortex?
Sex steroids
What is produced in the adrenal medulla?
Catecholamines
What is the rate limiting step in steroid hormone synthesis?
- Cholesterol -> Pregnenolone
- Side chain cleavage
Adrenal Medulla
- Derives from ectoderm (neural crest)
- Contain chromaffin cells
- Sympathetic innervation
Adrenal Cortex
- Develops from mesoderm
- Divided into three zones (zona glomerulosa, zona fasiculata, and zona reticularis)
Modified Fatty Acids
- Eicosanoids are derived from 20 carbons PUFA (arachidonic acid)
- Include the prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX)
- Autocrine and paracrine action
- Most prostaglandins have five membered rings with substituent determining the subclass (letter)
- Number following the third letter designates the number of double bonds in the two-side chain
Modified Fatty Acid Hormone Synthesis
- Arachidonic acid is released from the membrane by phospholipase A2 (Rate-limiting step)
- COX produces the cyclic endoperoxide intermediates (PGG2 and PGH2)
- Eicosanoids
- Anti-inflammatory steroids inhibit phospholipase A2
- COX inhibitor (aspirin)
Explain the difference between humoral hormonal, and neural.
- Humoral: response to changes in composition of extracellular fluids (levels of ion/nutrients in the blood)
- Hormonal: stimulated by other hormones (presence or absence)
- Neural: stimulated by nerves
Principle of homeostasis
- Hormone is released based on the requirement for a biological response
- Once response is met, secretion is inhibited to prevent over response
- Most endocrine systems have feedback loops to limit or regulate hormone synthesis and/or release
- Feedback can be direct or indirect via the CNS
Receptor Signaling
- Presence of specific protein receptor in cell is the target for hormone
- Receptors are subject to removal/inactivation
Protein based hormone signaling
- Prostaglandins included
- Short half-life
- Cell surface receptors
Steroid based hormone signaling
- Thyroid hormone included
- Long half-life
- Intracellular nuclear proteins
Explain the two domains of receptors.
- Ligand-binding domain (stereospecific)
- Effector domain that responds to the presence of the hormone and initiates biological response
Cell Surface Receptors
- Three domains:
1. Extracellular component
2. Membrane-spanning component (20-25 AA organized into an alpha-helix to cross the membrane)
3. Intracellular component - Can be a single polypeptide (N-terminus outside the cell, C-terminus inside)
- Can be composed of subunits (ion channels)
- Classified based on number of membrane spanning regions and cytoplasmic part response to ligand binding
- Ex: GPCRs
G-Protein Coupled Receptors (GPCRs)
- Most common, ligand and response specific
- Act via G protein complex to activate enzymes
- 7 transmembrane domains (single polypeptide chain)
- Engage second messengers (ex: IP3, DAG, Ca2+, cAMP) for signal amplification
- Ex: GnRH-R, muscarinic AChR
- Inactive G-proteins: three subunits in a heterotrimer (alpha, beta, gamma)
- Subunits (alpha and gamma) have lipid moieties binding them to the membrane
- GDP (guanosine diphosphate) is bound to the alpha subunit
- Ligand binds to the receptor -> GDP is replaced with GTP
- Receptor acts as the guanine nucleotide exchange factor (GEF)
- alpha-subunit dissociates and moves through the membrane to a nearby protein (enzyme, ion channel)
Tyrosine Kinase Receptors
- Single membrane spanning receptors
- Dimerize upon ligand binding
- Exception: IR and IGF-1R dimers of hemireceptors
- Kinase activity: main cytoplasmic constituent and initiator of signal transduction
- Main signaling pathway engaged by receptor tyrosine kinases (ex: MAP kinase cascade, protein kinase C pathway, JAK/STAT pathway)
- Each phosphorylation steps: amplification of the response (small concentration of hormone)
Ligand Gated Ion Channels
- Ion specific channels open when ligand binds to the receptor
- Rapid movement of ion along concentration gradient (first message)
- Ex: nicotinic AChR, 5-HT3R (serotonin)
- 5 Subunits, spanning the membrane 4 times to form a cylinder
Cell Surface Receptor Signaling
- Ligand binding to the exterior of the cell and initiate a signaling cascade on the interior of the cell that changes “physiology” in the target cell
- Can change: protein transport, protein synthesis, secretion, ion channels, gene expression
Nuclear Receptors
- Found in the nucleus or cytoplasm (will move to nucleus) of target cells
- May be bound to corepressor (chaperone) molecules which suppress DNA transcription
- Structure include a DNA-binding domain (highly conserved domain (C) and variable domain (D)) (regulation of gene expression/transcription)
- DNA-binding site consists of 2 zinc fingers
- Binds DNA at the hormone response element (HRE)
- Ligand binding domain is less conserved but adopts approximately the same three-dimensional structure in all the receptor (12 alpha-helices arranged in three layers)
- Regulates gene transcription
- Response can include an early and delayed response in transcription of target genes
Explain the receptor/hormone interaction.
What can affect the biological response?
- Concentration ligand [L]: rate of production, rate of degradation/elimination
- Number of available receptors on the cell [R]cell: sensitivity, competitive binding, saturation
Explain diabetes in regards to a problem with the receptor versus the ligand.
- Type 1: Insulin dependent (IDDM), normal R, no pancreatic beta-cells (no L)
- Type 2: Non-insulin dependent (NIDDM), impaired R function, increased circulating L
