Receptor Transduction Systems 2 Flashcards
what do GPCRs systems found in the cell membrane consist of?
- GPCR receptor protein itself
- G-protein (heterotrimeric, alpha-beta-gamma), alpha subunit binds GTP when active, hydrolyses to GDP to turn off signalling
- effector proteins including: enzymes, ion channels
why do we need GPCRs?
they allow conserved signalling machinery to generate incredibly complex responses
what types of responses do GPCRs allow?
- amplification
2. diversity
what does amplification consist of?
- one receptor may activate multiple G proteins
- one g-protein may activate multiple effector enzymes
what does diversity consist of?
- a single receptor may activate different classes of G-protein with unique signalling properties
- one G-protein may activate different types of effector
- G-protein heterotrimer components: alpha and beta-gamma subunits may activate different effectors
how are heterotrimeric G-proteins grouped?
they are grouped into 3 primary classes based on their downstream signalling properties
which are the types of heterotrimeric G-proteins?
- Gs family: activates cyclase to increase cAMP
- Gi family: inhibits adenylate cyclase to decrease cAMP
- Gq family: activates phospholipase C to produce IP3 and DAG
what do beta-adrenoceptors do?
they activate adenylate cyclase: ATP–> cyclic AMP (cAMP)
what are the effects of increased cAMP?
- heart (beta1): increase heart rate and force of heart beat
- lungs (beta2): relaxes bronchial smooth muscle
what are the effects of agonists in the lung?
- dilates bronchial smooth muscle
- eases respiration
- used in asthma
what are antagonists in the heart?
- competitive reversible antagonist
- slows heart rate and reduces force of beat
- used in cardiovascular disease e.g. hypertension
what activates alpha1-adrenoceptor?
epinephrine
where is alpha-adrenoceptor expressed?
in smooth muscle
why does alpha-adrenoceptor couples to Gq protein?
because it activates PLC to generate IP3 and DAG
how does alpha-adrenoceptor increases intracellular Ca2+ concentration?
by:
- release from SR (IP3)
- through membrane channels (DAG)
what does Ca2+ do?
stimulates smooth muscle contraction
what is prazosin?
a competitive reversible antagonist of the alpha1-adrenoceptor
what does prazosin do?
prevents contraction of smooth muscle in blood vessel wall
how does prazosin work?
it dilates blood vessels so blood pressure falls
what is prazosin used for?
to treat cardiovascular disease e.g. hypertension
other cell responses regulated by Gq Inositol-Phospholipid signalling
- liver - vasopressin - glycogen breakdown
- pancreas - acetylcholine - amylase secretion
- smooth muscle - acetylcholine - contraction
- blood platelets - thrombin - aggregation
what is a tyrosine kinase?
an enzyme that can transfer a phosphate group to a tyrosine residue in a protein
where is phosphorylation important?
in signal transduction to regulate enzyme activity
what do tyrosine kinase receptors link?
an extracellular ligand binding domain with an intracellular tyrosine kinase domain
what is dimerisation?
coupling by an agonist binding to 2 receptors
what is a receptor tyrosine kinases (RTKs)?
a cell membrane receptors containing a single TM domain
what activates RTKs?
hormones and growth factors e.g. insulin, AGF
what happens when RTKs activate?
upon receptor activation, they form a dimer and autophosphorylate
what happens after the formation of a dimer and autophosphorylation?
a kinase cascade is activates that ultimately phosphorylates a transcription factor
what do RTKs do?
regulate gene expression, growth, metabolism
examples of drugs that inhibit RTK signalling
- Imatinib (Gleevec)
- Lapatinib (tykerb)
- Trastuzumab
what is imatinib?
a small molecule tyrosine kinase inhibitor for chronic myelocytic leukemia
what is lapatinib?
a small molecule EGF receptor inhibitor approved in US for breast cancer
what is trastuzumab?
a monoclonal antibody against EGF used primarily again in breast cancer
