G protein families and subunits

See also Figure 13.18, Figure 16.11, Action of Epinephrine, G Protein Families and Subunits, G Proteins and Signal Transduction... 

See also G Protein Families and Subunits, Signal Transduction Agonists and Antagonists, G proteins in vision. Figure 12.13, Metabolic Control Mechanisms (from Chapter 12)... 

There is a large family of G proteins, and these are part of the superfamily of GTPases. The G protein family is classified according to sequence homology into four subfamihes, as illustrated in Table 43-3. There are 21 a, 5 P, and 8 y subunit genes. Various combinations of these subunits provide a large number of possible aPy and cyclase complexes. 

Neutrophil membranes contain inositol lipids, which comprise about 5-6% of the total membrane lipids. About 80% of these inositol lipids possess stearic acid (Cl8 0) at Cl and arachidonic acid (C20 4) at C2 positions. Phosphatidylinositol accounts for most of these lipids (90%), with smaller amounts of PIP (6%) and PIP 2 (4%), which are synthesised sequentially by the action of 4- and 5-specific kinases, respectively (see Fig. 6.6). Neutrophil membranes also possess a phosphatidylinositol-specific phospholipase C which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into Ins 1,4,5 P3 and DAG (Fig. 6.7). Both PLC-/3(/ 2) and PLC-y (72) families appear to be present in neutrophils. The coupling of receptor occupancy to PLC activation in neutrophils can be through a heterotrimeric G-protein, the mobile subunit of which has been termed G p. Evidence for this G-protein link comes from the following facts ... 

G-Protein Coupling. The heterotrimenc guanosine triphosphate (GTP) binding proteins, known as G-proteins, are a principal family of proteins serving to couple membrane receptors of the G-protein family to ionic and biochemical processes. The G-proteins are heterotrimers made of three families of subunits, o,/3. and y, which can interact specifically with discrete regions on G-protein-coupied receptors. This includes most receptors for neurotransmitters and polypeptide hormones (see Neuroregulators), G-protein-eoupled receptors also embrace the odorant receptor family and the rhodopsin-linked visual cascade. 

Strathmann, M., T.M. Wilkie, and M.I. Simon. 1989. Diversity of the G-protein family sequences from five additional alpha subunits in the mouse. Proc. Natl. Acad. Sci. USA 86 7407-7409. 

PertOfran desipramine. pertussis toxin (PTX) is elaborated by a bacterium Bordetella pertussis) and is a hexameric protein (4-5 subunits from A-B complex). It is a G-protein inactivator that binds to the ADP-ribosylation regulatory site of the G/Go family of subunits which couple negatively to adenylyl cyclase. The cellular responses blocked by PTX are varied, and typically include those due to 03 and opioid receptor type activation. The inactivation of this key regulatory unit explains some of the side-effects of whooping cough (caused by Bordetella pertussis) where production of this toxin is a main pathological factor. This toxin is an important pharmacological tool. 

The first system again makes use of yeast. It has been known for some time that S. cerevisiae can exist as two sexual types, a cells and a cells, which communicate with each other via sex pheromones, a-factor and a-factor. The receptors for these two pheromones are members of the 7-transmembrane family, although their amino acid sequences are quite distinct from their mammahan counterparts. The consequence of the binding of the pheromone to its receptor is to set in motion a complex set of biochemical events that lead, ultimately, to mating of the two opposite cell types. However, there are two principal events that can readily be detected. The cells undergo rapid, but transient, cell cycle arrest and express on their ceU surface a variety of proteins that aid in fusion of the mating types. Unlike their mammalian counterparts, the intracellular signal is transmitted via the (3- and -subunits of the trimeric G-protein complex and not by the a-subunit. A detailed description of this pathway... 

The structure of the ligand-free opsin bound to a synthetic peptide derived from the C-terminus of the a-subunit of transducin has recently been obtained [15], This structure has shown that the a5 helix of G t binds to a site in opsin that is opened by the movement of the cytoplasmic end of TM6 away from TM3 and towards TM5 (see above). The C-terminal domain of the G protein interacts with the extended conformation of R3.50, the short loop connecting TM7 and Hx8 and the inner side of the cytoplasmic TMs 5 and 6 (Figure 2.7). Notably, both the G protein family (positions i-2 and i-7 relative to the final amino acid) and TMs 5 (positions 5.61 and 5.65) and 6 (position 6.33) of class A GPCRs contain highly conserved hydrophobic amino adds that form key hydrophobic contacts between the receptor and the G protein. Notably, chemokine receptors also possess hydrophobic amino acids at these 5.61 (I 75% L 10% V 5%), 5.65 (L 90% I 5%) and 6.33 (A 75% L 5%) positions. It, thus, seems reasonable to assume that the mode of recognition of the G protein by the chemokine receptor family resembles this structure found for opsin [15]. 

GABAb receptors mediate the slow and prolonged physiological effects of the inhibitory neurotransmitter GABA. Functional GABAb receptors are comprised of two subunits, GABAbR1 and GABAbR2. Both subunits are G-protein-coupled receptors, which couple to the Gi/o family and are densely expressed at spinal nociceptive synapses. 

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

The 3 isozymes are activated by G protein-coupled receptors through two different mechanisms [2]. The first involves activated a-subunits of the Gq family of heterotrimeric G proteins (Gq, Gn, Gi4, G15/16). These subunits activate the (31, (33 and (34 PLC isozymes through direct interaction with a sequence in the C terminus. The domain on the Gqa-subunit that interacts with the (3 isozymes is located on a surface a-helix that is adjacent to the Switch III region, which undergoes a marked conformational change during activation. The second mechanism of G protein activation of PLC 3 isozymes involves (3y-subunits released from Gi/0 G proteins by their pertussis toxin-sensitive activation by certain receptors. The 3y-subunits activate the 32 and 33 PLC isozymes by interacting with a sequence between the conserved X and Y domains. 

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