PT  - JOURNAL ARTICLE
AU  - Vicky N. Jackson
AU  - Daljit S. Bahia
AU  - Graeme Milligan
TI  - Modulation of Relative Intrinsic Activity of Agonists at the<em>Alpha-</em>2A Adrenoceptor by Mutation of Residue 351 of G Protein G<sub>i1α</sub>
AID  - 10.1124/mol.55.2.195
DP  - 1999 Feb 01
TA  - Molecular Pharmacology
PG  - 195--201
VI  - 55
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/55/2/195.short
4100  - http://molpharm.aspetjournals.org/content/55/2/195.full
SO  - Mol Pharmacol1999 Feb 01; 55
AB  - Compared with epinephrine, the relative intrinsic activity of a series of partial agonists to activate fusion proteins between the porcine alpha-2A adrenoceptor and the α-subunit of Gi1 was reduced after a single-point mutation (Cys351Gly) in the G protein. Although UK14304 was close to a full agonist at the fusion construct containing wild-type (Cys351)Gi1α, it was a partial agonist at that containing Gly351Gi1α. Moreover, although clonidine functioned as a good partial agonist to activate the fusion protein containing Cys351Gi1α, it was essentially an antagonist at the Gly351Gi1α-containing fusion protein. By contrast, incorporation of Ile351Gi1α into the fusion protein resulted in all partial agonists displaying higher intrinsic activity relative to epinephrine to activate this fusion protein than the one containing the wild-type G protein sequence.  This is the first demonstration that the relative intrinsic activity of a series of agonists can be modified by a point mutation in a G protein rather than a receptor and indicates that the nature of a key contact site between a G protein and a receptor can selectively regulate partial agonist function. We provide a model for this based on the hydrophobicity of a key receptor-G protein α-subunit interaction interface.