Ga protein activation

This is achieved through the action of olfactory neurons. These hnk the olfactory bulb of the brain and the nasal cavity. Each olfactory neuron expresses one of 500-700 different kinds of odorant receptor (OR). ORs are G protein-coupled receptors. Binding of an odorant to a specific OR triggers activation of the Ga protein that is associated with the OR. The Ga protein activates adenyl cyclase, and the cAMP consequently opens a cAMP-gated ion channel. The channel allows entry of Na+ and Ca + into the neuron, thus triggering transmission of a nerve impulse to the brain. Our perception of particular smells is based on combinatorial activation of different ORs by different odorants in a sample that might have a complex mixmre of odorants. 

Detection of Ga Protein Activation by Measurement of Second Messengers 424... 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Tun C, Guo W, Nguyen H, Yun B, Libby RT, Morrison RS, Garden GA (2007) Activation of the extrinsic caspase pathway in cultured cortical neurons requires p53-mediated down-regulation of the X-linked inhibitor of apoptosis protein to induce apoptosis. J Neurochem 102 1206-1219... 

Kd 50 nM for GIRK [G-protein-activated inwardly rectifying K+ channel] activation) and persistent in the absence of competing Ga-GDP, Py-effector binding is not irreversible. 

The sequences of events that occur during activation of adenylate cyclase after receptor occupancy are shown in Figure 6.3. This scheme thus shows activation of a Gofc-type protein (i.e. a process that leads to the activation of adenylate cyclase), whereas similar processes will occur with a Ga protein, except that the interaction with adenylate cyclase will result in its inactivation. In the same way, activation of phospholipases by mobile Ga-type subunits will occur via similar mechanisms. In the unstimulated state, Gas (or Gcq) is bound to GDP. Binding of the receptor with its agonist induces a conformational change in the receptor that activates its G-protein. This stim-... 

The G-protein that has been termed Gp, and that is linked to phospholipase C activation, may in fact be Gaj 2 or Gc. 3. Ga is designated as the G-protein responsible for activation of phospholipase A2, which results in arachidonic acid release. Some experimental evidence indicates that, at least in HL-60 cells, different agonists can preferentially activate different phospholipases, and some of these are responsible for the activation of secretion. In neutrophils, the two pertussis-toxin-sensitive Ga-proteins (Gaj-2 and G j 3) have been identified by peptide mapping of proteolytic digests of the proteins, by peptide sequencing and by immunoblotting. Complementary-DNA clones for the mRNA of these two molecules have also been isolated from an HL-60 cDNA library. Gai-2 is five to ten times more abundant than Gai.3, the former component comprising 3% of the total plasma membrane proteins. It is possible that these two different Ga-subunits are coupled to different phospholipases (e.g. phospholipases C and D). Pertussis toxin inhibits the secretion of O2 after stimulation of neutrophils by fMet-Leu-Phe, but pertussis-toxin-insensitive G-proteins are also present in neutrophils. These may be members of the Gq family and may be involved in the activation of phospholipase Cp (see 6.3.1). 

Frank M, Thumer L, Lohse MJ, Bunnemann M (2005)G protein activation without subunit dissociation depends on a Ga.-specific region. J Biol Chem 280(26) 24584-24590 Gao Z, Li BS, Day YJ, Linden J (2001) A3 adenosine receptor activation triggers phosphorylation of protein kinase B and protects rat basophilic leukemia 2H3 mast cells from apoptosis. Mol Pharmacol 59(1) 76—82... 

Two of the Gy effector complexes that we describe in this chapter involve interactions between the Ga protein and RGS-like domains of the effector. As discussed in greater detail in Section V, many RGS domains exhibit GAP activity toward Ga. This is true for the major family of RGS domains whose members share substantial sequence similarity. The RGS-like domains of pll5RhoGEF and GRK2 belong to separate and distinct subgroups that bear only remote sequence similarity to the larger family of RGS GAPs, and bind to Ga in the mode characteristic of effectors. 

The catalytic glutamine at position 204 in Gail is a conserved feature in all functional Ga proteins, and in most members of the Ras superfamily (residue 61 in Ras). Mutations of this residue in Ga and Ras abolish GTPase activity, are constitutively active, and contribute to cellular transformation (Barbacid, 1987 Bourne et aL, 1991 Gilman, 1987). Further, GTPase activity of the... 

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