-
T/F
The type of receptor present on the target cell determines the effect
- TRUE
- receptors have different functions
-
cell membrane
consists of:
- phospholipids,
- cholesterols,
- proteins
-
2 types of communication for cells
- 1. intercellular (between)
- 2. intracellular (within)
-
Ligands
- 1st messengers
- bind to receptors
- exogenous (drugs)/ endogenous (hormones)
-
context: ligand activity
efficacy
ability of ligand to INITIATE a cellular effect
-
context: ligand activity
agonist
- affinity
- efficacy
- endogenous/exogenous
-
context: ligand activity
antagonist
- affinity
- NO efficacy- blocks agonist
- endogenous/exogenous
-
context: receptors
2 types and function
- cell membrane
- intracellular (inside)
- -modifies signal transduction pathway (on or off)
-
signal transduction pathway
- AKA intracellular signaling, second messenger system
- modification/chain of events of enzymes (kinase/phosphotases) or cell activity (open ion channels, transcription/translation)
-
context: regulation of receptors by Ligands
desensitization
- too much exposure to ligand = inactivate receptor
- ex: phosphorylation occurs
-
context: regulation of receptors by Ligands
down-regulation
high ligands = low amounts of receptors made
-
context: regulation of receptors by Ligands
up-regulation
low ligands = make more receptors
-
context: cellular signaling
5 INTERcellular signaling
- 1. cell to cell = gap junctions - small molecules
- 2. autocrine = release to self receptors - autocrine factors
- 3. paracrine = release to neighbor receptors - paracrine factors
- 4. nervous = neurons - neurotransmitters
- 5. endocrine (ex: neuroendocrine) = bloodstream (can go anywhere!) - hormones
- REMEMBER: (NECAP)
-
context: cellular signaling
2 types of receptors of INTRAcellular signaling
- 1. cell membrane receptors (hydrophilic) - (GPCR, enzyme-linked, ion channel-linked)
- 2. intracellular receptors (lipophilic) - (steroid, thyroid)
-
context: GPCR (cell membrane, intracellular)
other names
- AKA
- metabotropic receptors
- 7-transmembrane spanning receptor
-
context: GPCR (cell membrane, intracellular)
coupled with
-
context: GPCR (cell membrane, intracellular)
General scheme
- ligand and receptor -->transducers (G-protein) --> effectors (AC or PLC) --> second messengers to amplification (cAMP or Calcium/IP3)
- --> physiological response
-
context: GPCR (cell membrane, intracellular)
significance
- 2% of genome
- exogenous (senses) > endogenous (neurotransmitters/hormones)
-
context: GPCR (cell membrane, intracellular)
G- proteins
- heterotrimeric = 3 subunits (alpha, beta, gamma)
- activated when bound to GTP
- INTRINSIC GTPase activity = self-regulation
-
context: G- proteins
Gs va Gi
- s = stimulate AC
- i = inhibit AC
- AC= adenylyl cyclase - membrane bound enzyme
-
context: GPCR (cell membrane, intracellular)
Baseline activity???
- YES.
- Gi decreases from baseline.
- cAMP goes down by Gi activating PDE (phosphodiesterase) and deactivate AC
- both breaks down and stops making cAMP.
-
context: G-proteins
Gq
- activate PLC:
- --> IP3 --> Ca2+ (constricts smooth muscle around blood vessel)
2nd pathway: --> Dag --> kinase --> effects.
-
2 reasons GCPR are good drug targets
- 1) location: cell surface
- 2) ratio: few receptors = amplification after
-
4 GPCR disorders
- 1. mutation -genes = bad receptors, permanent off/on ex: inherited hypocalciuric hypercalcemia
- 2. processing error - gene ok, misfolding, permanent off/on ex: blindness
- 3. antibodies - receptor ok = bodies make antibodies that affect receptor (turn off/on) ex: Graves disease
- 4. toxins - structure and function ok, affect G PROTEIN (receptor off/on) ex: Cholera, Pertussis
-
context: enzyme-linked receptors/Tyrosine Kinase receptor (main)/Serine.Threonine receptors (less)
structure 4 parts
- 1. binding domain
- 2. transmembrane region
- 3. kinase domain
- 4. autophosphorylated region
-
context: enzyme-linked receptors/Tyrosine Kinase receptor (main)/Serine.Threonine receptors (less)
receptor activation/signal steps
- 1. receptors dimerize
- 2. receptors autophosphorylate (add phosphate groups)
- 3. activation of intracellular kinases (cascades)/ proteins (RAS- 25% mutated in cancer patients)
- 4. cell proliferation
-
context: enzyme-linked receptors/Tyrosine Kinase receptor (main)/Serine.Threonine receptors (less)
3 Endogenous Ligands
- 1. insulin (hormone) - intake glucose/a.a, replication/translation
- 2. growth factors (hormone/paracrine) - cell replication/differentiation
- 3. cytokines (hormone/paracrine) - cell replication/differentiation + inflammation
-
context: enzyme-linked receptors/Tyrosine Kinase receptor (main)/Serine.Threonine receptors (less)
RAS
- 1 monomeric G-Protein
- no intrinsic GTPase
- activates Mitogen-Activated Protein kinase cascade
-
context: ion channel-linked receptors/ligand-gated/ionotropic
signaling
- 1. ligand opens channel
- 2. ion diffuses
-
context: ion channel-linked receptors/ligand-gated/ionotropic
Endogenous Ligands (4)
- 1. ACh (nicotinic) - Na+ goes in = contraction at neuromuscular junction (skeletal)
- 2. Serotonin (5HT3) - cations = muscular contractions at intestines and stomach (smooth)
- 3. Glutamate (NMDA) - cations = increases neuronal activity
- 4. GABAA - Cl- goes in = decreases neuronal activity
-
context: intracellular receptors/NHR/ Cytosolic
signaling steps (3)
- 1. ligand diffuses through membrane
- 2. binds in cytosol or nucleus
- 3. complex migrates to nucleus
-
context: intracellular receptors/NHR/ Cytosolic
Endogenous ligands (3)
- 1. Glucocorticoids (corticosteroids)
- 2. Estrogen, Progesterone
- 3. Thyroid hormones
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