Chapter Three Text Molecular Basis Of Hormone Action Flashcards
What does the binding of a receptor induce
A conformational change in the receptor that initiates downstream signaling
What determines the scope of hormone action
Tissue distribution of receptor
How does downstream signaling differ
It differs across cell types to produce potentially diverse hormonal effects
How is control of hormone receptors exerted
Through the constant synthesis, degradation and localization of hormone receptors
What are the two hormone receptor super families?
Water soluble hormones and lipid soluble hormones
Characteristics of water soluble hormones (4)
Plasma membrane is impenetrable
Cell-surface receptors transducer signal thorough membrane
Activate intracellular signaling pathways
Fast responses (seconds) as well as slow ones
Characteristics of lipid soluble hormones (4)
Pass through plasma membrane
Receptors function as transcription factors in the nucleus
Activate or repress gene expression
Tend to be slow responses (hours-days)
Three binding characteristics of binding receptors
High affinity
Reversible binding
Specificity
How is signal transducer for cell-surface receptor
When hormone binds to receptor, the cascade of cytoplasmic responses is mediated through protein phosphorylation by kinase enzymes or the generation of second messengers via coupling to G proteins
Two major groups of cell-surface receptors
Tyrosine kinase receptors and G-protein coupled receptors
Tyrosine kinase receptors
Signal via phosphorylation of the amino acid, tyrosine
Go-protein-coupled receptors
Activate or inhibit adenylate Cyclase and/or phospho lipase C (PLC)
Signal via second messenger: cyclic adenosine monophosphate (cAMP), inositol triphosphate (IP3), diacylglycerol (DAG) and intracellular calcium
Signal via phosphorylation of serine and threonine amino acids
How does protein phosphorylation happen
Phosphate group is donated from ATP during catalysis by the kinase enzyme. It is accepted by the polar hydroxyl group of serine, threonine, or tyrosine and causes a conformational change in the 3D shape of the protein
Two ways through phosphorylation of TK receptors can occur
Intrinsic TK activity located in the Cytosolic domain of the receptor
Separate TKs recruited after receptor activation
How do intrinsic TK receptors phosphorylate
They auto phosphorylate upon binding of the appropriate hormone
Which amino acids can be phosphorylated
Serine, threonine and tyrosine
How do G protein coupled receptors work
Couple to G proteins at the inner surface of the cell membrane, leading to the generation of intracellular second messengers such as adenosine-3’, 5’-cAMP, diacylglycerol (DAG), and IP3. G protein receptors also exist for glutamate, thrombin, odorants, and the visual transduction of light.
What does G protein coupled receptor signaling involve
Hydrolysis of GTP to GDP . G peoteins exist in the cell membrane as heterotrimeric complexes with alpha, beta and gamma subunits. Beta and gamma subunits have such affinity that functional units are Galoha and Gbeta/gamma. Hormone binding results in conformational change in alpha subunit, leading to an exchange of GDP for GTP.
How do second messenger pathways work?
Activation of membrane bound adenylate Cyclase catalyzes the conversion of ATP to cAMP. cAMP interacts with protein kinase Aro unmask its catalytic site, which phosphorylates serine and threonine residues on a transcription factor called cAMP response element binding protein.
What does CREB do on e it has been phosphorylated?
Translocation to the nucleus where it bonds to a short palindromic sequence in the regulatory regions of cAMP-regulated genes
How is cAMP response terminated?
By a large family of phosphodiester ashes, including phosphorylation by PKA in a negative feedback loop. cAMP is hydrolyzed to inactive 5’-AMP
Which hormones recruit G protein complexes with the Gqalpha subunit
TRH, GnRH, oxytocin
What does Gqalpha subunit activate
Membrane-associated PLC, which catalyzes the conversion of PI 4,5-bi phosphate (PIP2) to DAG and IP3.
What does IP3 do?
Stimulates thr transient release of calcium from the ER to activate several calcium-sensitive enzymes, including isoforms of protein kinase C and proteins like calmodulin. The calcium ions also activate Cytosolic guanylate Cyclase, which catalyzes the formation of cyclic guanosine monophosphate (cGMP).
What is the target of DGA signaling
PKC, which activates phospho lipase A2 to liberate arachnid oriC acid from phospholipids and generate potent eicosanoids, including thromboxanes, leucotrienes, lipoxons and prostaglandins.
What happens when ligands bind to nuclear receptors
The receptors bind DNA and function as transcription factors. Biological responses of nuclear receptors are slow.
Orphan nuclear receptors
Have no endogenous ligand
Why do ligands for nuclear receptors undergo enzymatic modification within the target cell
To convert circulating hormone into a more or less potent metabolite prior to receptor binding.
What do unbound steroid hormone receptors associate with in their resting state
Heat-shock proteins
What do heat shock proteins do to steroid hormone binding receptors
They obscure the DNA binding domain so that they are considered incapable of bonding the genome.
What happens to heat shock proteins when a steroid binds
Conformational change causes their dissociation
What ahopens when heat shock peoteins dissociate from receptors
Two polypeptide loops are revealed that are stabilized by zinc fingers. Once two steroid receptors have dimerized, the motifs bind to target DNA at the specific hormone response element (HRE).
Where is thyroid hormone receptor located
In the nucleus bound to DNA at the thyroid hormone response element
What happens to unliganded thyroid hormone receptor in the absence of hormone
TR dimerized with the retinoid X receptor and tends to recruit nuclear proteins that inhibit transcription.
What happens when thyroid hormone binds to receptor
Nuclear proteins and retinoid X receptor dissociate, and TR recruits transcriptional co-activators. A sequence of events recruit DNA-dependent RNA polymerase, which leads to transcription.
Variant nuclear receptors
Have atypical DNA binding domains and potentially function via indirect interaction with genome
Pituitary-specific transcription factor 1 regulates what
The expression of genes encoding GH, PRL, and the beta subunits of TSH. PIT1 mutations show reduced or absent levels of these hormones, causing short stature, and are at risk of congenital secondary hypothyroidism with severe learning disability
What transcription factors does the development of the pancreas depend on?
Pancreas duodenal homeobox factor 1[PDX1] and several members of hepatocites nuclear factor (HNF). Mutations here cause monogenic diabetes mellifluous. These patients may never accrue a normal number of beta cells, which don’t function properly.
Which hormones act via cell-surface receptors
Peptide hormones and catecholamines
Which hormones act via nuclear receptors
Steroid and thyroid hormones
Mutations in genes encoding any part of of the cascade from hormone receptor to action can result in?
Under active or over active endocrinopathy, or potentially tumor formation.
