Complex Signalling pathways Flashcards
Binding positions of Rhodspin like, Secretin Like and Glutamate like
- Smaller molecules bind in the cleft of TM segments
- larger molecules often bind to th N-terminus or ECL
GTPase activity
GTPase activity of the alpha subunit is increased when bound to effector proteins
G protein selectivity
Certain receptors are more likely to bind to other G- proteins due to complementary recognition sequences
RHO system
Rho is a monomeric G protein activated by alpha subunits of the 12/13 subclass. Activated 12/13 subunits bind to GEFS, GEFS then bind RHO promoting guanonucleotide exchange. RHO then binds ROCK which inhibits myosin light chain phosphatase activity, PROMOTING CONTRACTILITY.
Termination of signalling
- Degradation or removal of agonists
- Receptor desensitisation/internalisation
- GTPase activity
- Degradation of second messengers
Heterologous desensitization
Non-specific and mediated by pKa and pKc. Serine and threonine residues in the intracellular loops and N-terminus are phosphoylated which makes G-Protein coupling less likely.
Residues to be phosphorylated are located in the THIRD INTRACELLULAR LOOP
Homologous Desensitization
GRK’s phosphorylate specific threonine and serine residues located in the C-terminal tail. Phosphorylation primes the receptor for B-arrestin binding. B-arrestin the recruits endocytotic mediatiors, Clathrin and Clathrin Adaptor Protein.
Post-endocytosis Outcomes
- Enternalized proteins are either dephosphorylated and returned to the plasma membrane or degraded via a lysosoma or 26S proteasome pathway
Signal Maintenance of internalized receptors
The signal is generated at the plasma membrane and continues signalling in early endosomes through formation of RAS–RAF–MEK–ERK (RAS–RAF–MAPK/ERK kinase (also known as MAPKK)–extracellular signal-regulated kinase) complexes bound to the growth factor receptor-bound 2 (GRB2) adaptor for RTKs or β-arrestin for GPCRs. Activated ERK is released from the endosome and translocates to the nucleus to phosphorylate its targets. c
Roles of B-arrestin
- Promotes degredation of 2nd messengers by recruiting phosphodiesterases and DAG kinase to the signalling site
- Directly recruits and promotes a second wave of B-arrestin dependent, G protein independent signalling
pKa sequence
Arg-Arg-X-Ser/Thr