Drug interactions with receptors and ion channels: Signalling mechanisms Flashcards Preview

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Flashcards in Drug interactions with receptors and ion channels: Signalling mechanisms Deck (12)
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Adenylyl cyclase

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.


Cholera toxin

Causes ADP-ribosylation of αs
- inhibits GTPase activity of αs, causes sustained activation of adenylate cyclase.


Pertussis toxin

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[2]- both cleavage products (DAG & IP[3] ) act as second messengers.


Diacylglycerol (DAG)

Stimulates membrane-bound protein kinase C -> which modifies properties of various proteins, such as ion channels, by phosphorylation.


Inositol 1,4,5-triphosphate ( IP[3] )

Causes release of Ca2+ from endoplasmic reticulum
Rapidly metabolized
- by phosphorylation to IP[4]
- by dephosphorylation successively to IP[2], IP[1] and inositol.



Uncompetitively inhibits the phosphatase responsible for converting IP[1] 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.


Heterologous desensitiztion

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.


Homologous desensitization

β-adrenoceptor kinase (βARK) can phosphorylate agonist occupied β2 receptors at the end of the C terminal domain.
Phosphorylation increases the affinity of the β2 receptor for the protein β-arrestin.
Binding of β-arrestin uncouples the receptor from the α subunit of Gs.

Takes place with high concentrations of ligand.
Homologous as βARK only works on agonist-occupied receptors- so this desensitisation does not affect any other receptors that might be present.