SM_174b: Mechanisms of Hormone Action Flashcards
Hormones may act on ____ or ____ receptors
Hormones may act on membrane or nuclear receptors
- Receptors mediate messages within the cell in response to the binding of a ligand
- Disease causes when excess / deficient hormone or impaired / hyperactive receptor
Ligands for nuclear receptors are ____, ____, and ____
Ligands for nuclear receptors are small, lipophilic, and synthesized by enzymes from precursors / sourced exogenously
- < 1000 daltons
- Steroid hormones (1,25-Vitamin D, thyroxine, estrogen, testosterone, progesterone, aldosterone, cortisol)
Describe the domains of nuclear receptors
Domains of nuclear receptors
- A/B: N-terminal domain
- C: DNA binding domain
- D: hinge region domain
- E: ligand binding domain
- F: C terminal DNA binding domain
Describe the steps of nuclear receptor activation
Nuclear receptor activation
- Ligand binding
- For most receptors: dimerization to homo- or heterodimers
- Binding to hormone response element: receptor specific DNA sequence specific to the receptor close to promoters of genes regulated by the particular receptor
- Optional: binding of co-activator(s) or co-repressor(s)
- Activation of repression of gene transcription
Signaling via nuclear receptors can be regulated at the level of the ____ or ____ as well as the presence of coactivators or corepressors
Signaling via nuclear receptors can be regulated at the level of the ligand or receptor as well as the presence of coactivators or corepressors
- Ligand levels: precursor availability, synthesis, secretion, activation, deactivation, elimination
Nuclear receptors regulate gene transcription via _____ and _____
Nuclear receptors regulate gene transcription via ligand-dependent activation and ligand-dependent negative regulation of transcription
An example of a nuclear receptor is ____
An example of a nuclear receptor is resistance to thyroid hormone at the thyroid hormone receptor beta
- Presents as goiter and tachycardia (also others)
- Elevated thyroid hormone and normal TSH level
- Most common mutation is inactivating mutation in thyroid hormone beta receptor
Complete androgen insensitivity syndrome involves a mutation in ____ that causes ____ and subsequent ____
Complete androgen insensitivity syndrome involves a mutation in androgen receptor that causes inability for cells to sense testosterone and subsequent conversion of testosterone to estrogen
- 46XY, genetically male, phenotypically female
Complete androgen insensitivity syndrome is often discovered at ____ due to ____
Complete androgen insensitivity syndrome is often discovered at puberty due to the absence of menses
Hereditary Vitamin D resistance rickets type 2 is due to ____
Hereditary Vitamin D resistance rickets type 2 is due to an inactivating mutation in Vitamin D receptor
- Vitamin D resistance: rickets, alopecia, variable degree of hypocalcemia, secondary hyperparathyroidism, high levels of 1,25(OH)2-vitamin-D3
Describe the types of membrane receptors
Membrane receptors
- Receptor tyrosine kinases: insulin receptor
- Receptor serine / threonine kinases
- Cytokine receptors
- G-protein coupled receptors
- Ligand-gated ion channels (nicotinic ACh-R)
- Receptor guanlyate cyclase
Receptor tyrosine kinases have components of ____, ____, and ____
Receptor tyrosine kinases have components of extracellular ligand-binding domain, single transmembrane domain, and intracellular tyrosine kinase catalytic domain
- Examples of ligands: insulin, epidermal growth factor, platelet-derived growth factor
- Most sequence / structural variation in extracellular domain
Receptor tyrosine kinases require ____ for activity
Receptor tyrosine kinases require dimerization (homodimers or heterodimers) for activity
- Ligand binding leads to tyrosine kinase activation and downstream phosphorylation and signaling events
- Multiple variations: pre-existing dimers or large complexes that need one or multiple ligands to induce activity
Donohue syndrome (leprechaunism) is caused by a mutation in the ____ receptor which is a ____
Donohue syndrome (leprechaunism) is caused by a mutation in the insulin receptor which is a receptor tyrosine kinase
- Impaired binding or signaling via mutations in insulin receptor (insulin resistance)
- Most individuals die young
_____ have the same structure as receptor tyrosine kinases except these receptors phosphorylate serine / threonine
Receptor serine / threonine kinases have the same structure as receptor tyrosine kinases except these receptors phosphorylate serine / threonine
- Two types that interact to mediate signaling as dimers: type I (12 genes), type II (5 genes)
- Example: TGF-beta
Cytokine activated receptors are like other tyrosine kinases but signaling occurs via associated ____
Cytokine activated receptors are like other tyrosine kinases but signaling occurs via associated tyrosine kinase associated proteins (Janus kinase / JAKs)
- Growth hormone: growth
- Prolactin: reproduction / lactation
- Leptin: suppresses appetite and regulates metabolism
Growth hormone receptor mutation (cytokine receptor) lead to ____, ____, and ____
Growth hormone receptor mutation (cytokine receptor) lead to laron dwarfism, insensitivity to growth hormone, and reported resistance to diabetes and cancer
(autosomal recessive)
Leptin receptor is a ____ and inactivating mutations lead to ____ and ____
Leptin receptor is a cytokine receptor and inactivating mutations lead to early onset morbid obesity and hyperphagia
(autosomal recessive)
Describe GPCRs
GPCRs
- 7 transmembrane spanning helices
- Each GPCR is coupled intracellularly to heterotrimeric protein: G protein (alpha, beta, gamma subunits)
- Extracellular domain determines ligand specificity
- Intracellular domain determines function via G protein specificity
Gs proteins function to ____
Gs proteins function to stimulate cAMP production via adenylate cyclase
Gi proteins function to ____
Gi proteins function to inhibit cAMP production by adenylate cyclase
Gq proteins function to ____
Gq proteins function to induce phospholipase C mediated cleavage of PIP2 to IP3 and DAG
- IP3: ligand for ligand-gated ER bound Ca channels
- DAG: ligand for Ser/Thr kinase receptors
Describe receptors that use the non-classical signaling pathway through Gq
Non-classical signaling pathway through Gq
- 5-HT2 serotonergic receptors
- Alpha-1 adrenergic receptor
- Vasopressin receptor
- Angiotensin II receptor type 1
GPCRs are desensitized / downregulated by ____ or ____
GPCRs are desensitized / downregulated by phosphorylation or endocytosis
Nephrogenic diabetes insipidus results from a mutation in the ____ receptor which is a ____
Nephrogenic diabetes insipidus results from a mutation in the Vasopressin 2 receptor which is a GPCR
Autosomal dominant loss of function in a Ca sensing receptor which is a ____ causes ____
Autosomal dominant loss of function in a Ca sensing receptor which is a GPCR causes familial hypocalciuric hypercalcemia
Gain of function in TSH receptor which is a ____ cause ____
Gain of function in TSH receptor which is a GPCR cause hyperfunctioning thyroid nodules (toxic adenomas) leading to hyperthyroidism
Graves disease results from ____
Graves disease results from activating antibodies to TSH receptor
- Autoantibodies to receptors can be inhibiting or activating and lead to disease
- Gain of function
Ligand-gated ion channels act as ____
Ligand-gated ion channels act as ion channels for a specific ion
- Commonly either Na, Ca, K in response to ligand binding
- IP3 gated Ca channel
