15 | Hormone/Receptor Flashcards
hormone
substance secreted directly into the blood
by specialized cells
in response to a specific stimulus
which then influence other type(s) of cells
hormone-receptor interaction characteristics (6)
highly specific
high affinity
saturable (max binding capacity)
simple, bimolecular, reversible reaction
only in responsive tissue
may/may not need full saturation for full bio response
[GPCR, kinase-linked rec, steroid rec, thyroid hormone rec (not TSH)]
dissociation constant Kd
equation, 3 characteristics
Kd=[H][R]/[HR]
when [H]=Kd half of the receptors are bound to hormone
[H]*10 (above Kd) – 90% receptor occupancy
[H]/10 (of Kd) – 10% receptor occupancy
hormone types that interact with cell surface receptors (2)
peptide hormones
amines
-too polar, too large
cell surface receptor groups (2)
7 membrane-spanning domains (GPCR)
single membrane-spanning domain (enzyme linked)
role of G-proteins
membrane associated guanine nucleotide binding proteins
couple hormone binding to a receptor to effector modulation
Ga subunit is a GTPase (GDP+Pi)
G-protein + adenylase cyclase
mechanism
- activation of AC mediated by Gsa (regulatory, stimulatory)
- AC catalyzes formation of cAMP
- cAMP activates PKA by binding to regulatory subunits, releasing catalytic subunits
ligands that use cAMP as a secondary messenger (11 + 4)
ACTH ADH EPI/NE (catechol B-rec) glucagon glycoprotein hormones (LH, TSH, FSH, hCG) histamine MSH PG's PTH secretin VIP
G-protein + phospholipase C
mechanism
- Gqa activates PLC
- PLC cleaves PIP2 (membrane associated inositol phospholipid) to DAG + IP3
- IP3 stimulates release of Ca2+ from storage
- DAG (retained in membrane) associated with PKC, activates it in presence of Ca2+
phosphoinositol (PI) 3-kinase action
- PIP3-kinase phosphorylates PIP2 to PIP3
- PIP3 interacts with protein kinases (PDKs)
- PDKs travel to membrane, activate enzyme Akt
- Akt can phosphorylate target proteins (i.e. transcription factors)
G-protein + phosphodiesterase
Gta (in photoreceptors)
cGMP -> GMP
cAMP -> AMP
1TMD - tyrosine kinase rec
intrinsic tyrosine kinase activity
- binding dimerizes agonist/receptor complex
- autophosphorylation
- autophos inc. kinase activity and inc. afficity for associated substrates
- substrates are phos., con’t signaling
1TMD - serine/threonine kinase rec
- ligand binding, dimerize, phosphorylate cytoplasmic “Smads”
- Smads regulate gene transcription in the nucleus
1TMD - guanylate cyclase rec
- binding inc cytoplasmic cGMP
- cGMP mediates further action (i.e. PKG)
1TMD - cytokine rec family
- lacks intrinsic enzyme activity
- associate with soluble cytoplasmic tyrosine kinases (JAKs) with ligand binding/dimerization
- JAKs/DimRec activated, phos STATs (signal transducers and activators or transcription)
- STATs dimerize, travel to nucleus
1TMD - MAP kinase paths
MAP (mitogen activated protein)
- cascade of protein kinase reactions
- roles in cell proliferation in response to GF stimulation
receptor-mediated endocytosis
hormone/receptor complexes clustered in clathrin-coated pit region
- invaginate, pinch off, form coated vesicles
- targets to lysosome for degradation (hormones)
- receptors typically recycled to PM
intracellular rec - ligands
steroid hormones (TH, androgens)
- lipophillic
- bind to receptors in cytoplasm or nucleus
cytoplasmic steroid hormone/receptor complex
[steroid hormones - cortisol, aldo - androgens]
- receptor associated with HSP90, prevent interaction with DNA w/out ligand
- ligand binding dissociates
- H/R complexes dimerize, move to nucleus, interact with HREs
nuclear steroid hormone/receptor complex
[THs, Vit D derivatives)
- receptors associate with HREs w/out hormone
- alone, associated with nuclear proteins
- ligand binding releases nuclear proteins
- new nuclear proteins can now bind
- complex can promote activation or suppression of transcription targets
hormone response elements (HREs)
- palindromic sequences (inverted repeat)
- H/R dimerization for interaction
- binding initiates or suppresses transcription of nearby genes
kinase-linked ligands (10)
insulin, IGF-1, EGF, PDGF, GH mullerian inh substance, inhibin ANP EPO prolactin [insulin, growth factors, ANP (no steroids)]
intracellular receptor sequence
[3 structural domains]
C term hormone binding
central DNA binding (Cys residues, form Zn fingers, recognize specific HRE’s)
variable N term transcription factor binding
steroid hormone vs. protein hormone
not stored vs. stored
carrier-bound transport vs. soluble
interior rec vs. cell surface rec
passive diffusion into cell vs. receptor mediated endocytosis
