Flashcards in Drug interactions with receptors and ion channels: Signalling mechanisms Deck (12):
Generates cAMP which controls cell functions through protein kinase A.
Activated by e.g β1 adrenoceptor via Gs
Inhibited by e.g α2 adrenoceptor via Gi
NB βγ complex can itself be inhibitory, through the mopping up of free αs.
Causes ADP-ribosylation of αs
- inhibits GTPase activity of αs, causes sustained activation of adenylate cyclase.
Causes ADP-ribosylation of αi.
Prevents activation of αi in response to receptor stimulation.
Mimics γ phosphate of GTP
Causes persistant activation of G proteins
Phospholipase C (PLC)
Activated via Gq and G11, by e.g ACh at muscarinic receptors, noradrenaline at α1 receptors, substance P.
Cleaves PIP- both cleavage products (DAG & IP ) act as second messengers.
Stimulates membrane-bound protein kinase C -> which modifies properties of various proteins, such as ion channels, by phosphorylation.
Inositol 1,4,5-triphosphate ( IP )
Causes release of Ca2+ from endoplasmic reticulum
- by phosphorylation to IP
- by dephosphorylation successively to IP, IP and inositol.
Uncompetitively inhibits the phosphatase responsible for converting IP to inositol.
- thereby blocks recycling of inositol
Brain cannot take up plasma inositol (cannot cross BBB) and so depends heavily on inositol recycling to allow signalling through receptors that use IP3.
Used in treatment of manic depression (schizophrenia)
Inhibitors of tyrosine kinases.
May prove useful for controlling neoplastic growth
- RTKs regulate cell proliferation & differentiation
- v-erbB (viral oncogene) encodes a truncated, constitutively activated EGF receptor
- v-sis (viral oncogene) encoded a PDGF chain
Desensitization of the β2 adrenoceptor
(3 main processes)
1) Uncoupling of receptor from its G protein. Seconds to minutes. Involves 2 separate types of phosphorylation resulting in heterologous and homologous desensitisation.
2) Sequestration of receptors. Receptors removed from plasma membrane by endocytosis, transferred to vesicles in cytoplasm. Can be shuttled back to plasma membrane or destroyed in lysosomes. Minutes
3) Down regulation. Possible due to reduced receptor synthesis by an effect of PKA on mRNA stability. Longer term, minutes to hours.
Receptor disproportionately stimulated -> large rise activity of PKA which is able to phosphorylate the β2 receptor itself, at sites:
- on the third cytoplasmic loop
- on the first part of the C terminal domain.
Phosphorylation uncouples the receptor from the α subunit of Gs.
Takes place with low concentrations of ligand.
Heterologous as PKA can also phosphorylate other receptors with similar amino acid sequences to β2- other receptors than β2 can be desensitized without first being stimulated by ligand binding.