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G beta-gamma[edit]

Function[edit]

The βγ complex is an essential element in the G protein coupled receptor (GPCR) signaling cascade. It has two main states for which it performs different functions. When Gβγ is interacting with Gα it functions as a negative regulator. In the heterotrimer form, the βγ dimer increases the affinity of Gα for GDP, which causes the G protein to be in an inactive state[1] To become active the nucleotide exchange must be induced by the GPCR . Studies have shown that it is the βγ dimer that demonstrates specificity for the appropriate receptor [2] [3] and that the γ subunit actually enhances the interaction of the Gα subunit with the GPCR [3]. The GPCR is activated by an extracellular ligand and subsequently activates the G protein heterotrimer by causing a conformational change in the Gα subunit. This causes the replacement of GDP with GTP as well as the physical dissociation of the Gα and the Gβγ complex [4]. Once separate, both Gα and Gβγ are free to participate in their own separate signaling pathways. The Gβγ does not go through any conformational changes when it dissociates from Gα and it acts as a signaling molecule as a dimer [5]. The dimer has been found to interact with many different effector molecules by protein-protein interactions. Different combinations of the Gβ and Gγ subtypes can influence different effectors and work exclusively or synergistically with the Gα subunit [6].

βγ signalling is diverse, inhibiting or activating many downstream events depending on its interaction with different effectors. It has been shown the βγ regulates ion channels, such as G protein–gated inward rectifier channels (Logothetis), as well as calcium channels[7] . Another example of Gβγ signaling is its effect of activating or inhibiting adenylyl cyclase [8] leading to the intracellular increase or decrease of the secondary messenger cyclic AMP. For more examples of βγ signaling see table[6]. However, the full extent of beta gamma signaling has not yet been discovered.

Effector Signalling effect
GIRK2 activation
GIRK4 activation
N-type calcium channel inhibition
P/Q-type calcium channels inhibition
Phospholipase A activation
PLCβ1 activation
PLCβ2 activation
PLCβ3 activation
Adenylyl cyclase Type l, lll, V, Vl, Vll inhibition
Adenylyl cyclase Type ll, IV activation
PI3K inhibition
βARK1 activation
βARK2 activation
Shc phosphorylation activation
Raf-1 activation
Ras exchange factor activation
Bruton's tyrosine kinase activation
Tsk tyrosine kinase activation
ARF/endosome fusion activation
Plasma membrane Ca2+ pump activation
p21-activated protein kinase inhibition
SNAP25 inhibition
P-Rex1 Rac GEF activation

References[edit]

  1. ^ Brandt D., Ross E. (1985). GTPase activity of the stimulatory GTP-binding regulatory protein of adenylate cyclase, Gs : accumulation of turnover of enzyme-nucleotide intermediates The Journal of Biological Chemistry 260:266–272
  2. ^ Im MJ, Holzhofer A, Bottinger H, Pfeuffer T, Helmreich EJM. (1988). Interactions of pure βγ-subunits of G-proteins with purified β1-adrenoceptor FEBS Lett 227:225-229.
  3. ^ a b Kisselev, O., and Gautam, N. (1993). Specific interaction with rhodopsin is dependent on the γ subunit type in a G protein. J. Biol. Chem. 268: 24 519 – 24 522.
  4. ^ Digby G. J., Lober R. M., Sethi P. R., Lambert N. A. (2006). Some G protein heterotrimers physically dissociate in living cells. Proceedings of the National Academy of Sciences. 103:17789–17794.
  5. ^ Lin Y., & Smrcka A. V.(2011). Understanding Molecular Recognition by G protein Subunits on the Path to Pharmacological Targeting. Mol Pharmacol, Vol 80. No. 4 doi: 80:551–557, 2011
  6. ^ a b Clapham, D. E., & Neer, E. J. (1997).G protein βγ subunits. Annu. Rev. Pharmacol. Toxicol., 37, 167-203.
  7. ^ Ikeda S. R. (1996).Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380:255–258
  8. ^ Tang W., Gilman A. G. (1991).[ http://www.jstor.org.ezproxy.library.dal.ca/stable/2879439 Type-specific regulation of adenylyl cyclase by G protein βγ subunits.] Science 254:1500–1503

References[edit]