Disease relevance of Galpha49B

• These proteins represent a new class of G alpha subunits because they lack both high amino acid identity with other G alpha proteins and the pertussis toxin ADP ribosylation site [1].
• Targeted expression of either a stimulatory (Galpha(s)) or inhibitory (Galpha(i)) Galpha subunit, or tetanus toxin light chain (TNT) in dopamine and serotonin neurons of living flies blocked behavioral sensitization to repeated cocaine exposures [2].
• Vaccinia virus systems for expression of G alpha genes in S49 cells [3].

High impact information on Galpha49B

• The GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass [4].
• Upon ligand binding, the transmitter receptors interact with heterotrimeric G proteins, allowing G alpha and G beta gamma subunits to disengage [5].
• Their ability to dampen signalling via Galphai-, Galphaq- and Galpha12/13-coupled pathways makes them crucial players in mediating the multitude of cellular processes controlled by heterotrimeric G proteins [6].
• We show here that, in Drosophila, both functions require the Galpha interaction partner Ric-8 [7].
• During asymmetric cell division, this leads to various defects: apico-basal polarity is not maintained, mitotic spindles are misoriented and the size of the two daughter cells becomes nearly equal. ric-8 mutants also have defects in gastrulation that resemble mutants in the Galpha protein concertina or the extracellular ligand foldedgastrulation [7].

Biological context of Galpha49B

• We examined the roles of the Drosophila Gq alpha proteins (DGq) in the phototransduction pathway [8].
• An affinity-purified anti-DGq alpha immunoglobulin blocked the light-dependent GTP hydrolysis activity associated with Drosophila head membranes in vitro, suggesting that rhodopsin stimulated DGq [8].
• Molecular genetic dissection together with detailed kinetic analysis enabled us to characterize the translocation cycle and to unravel how signaling molecules that interact with Gqalpha affect these processes [9].
• We have uncovered three duplicated exons in dgq by scanning the GenBank data base for unrecognized coding sequences [10].
• Gq alpha protein function in vivo: genetic dissection of its role in photoreceptor cell physiology [11].

Anatomical context of Galpha49B

• The DGq proteins immunolocalized to the ocelli and all eight retinular photoreceptor cell rhabdomeres [8].
• Here we show, using live Drosophila flies, that light causes massive and reversible translocation of the visual Gqalpha to the cytosol, associated with marked architectural changes in the signaling compartment [9].
• Epistatic analysis showed that Gqalpha is necessary but not sufficient to bring about the morphological changes in the signaling organelle [9].
• We examined the in vivo splicing of dgq in adult flies and find that, in all but the male gonads, only two isoforms are expressed [10].
• A splice variant of Galphaq, dgqalpha3, is expressed in early axonal growth cones, which go to form the commissures in the Drosophila embryonic CNS [12].

Associations of Galpha49B with chemical compounds

• Although the role of the G alpha subunit in effector activation, guanine nucleotide exchange and GTP hydrolysis has been well studied, the cellular functions of the G beta subunits are less well understood [13].
• In addition, we show that (i) the specific PLC activity is a key factor determining the photoreceptor sensitivity; (ii) the catalytic activity and response termination are separable functions of PLC; and (iii) a mutation in the putative G alpha-interacting C2 domain causes a preferentially strong defect in latency [14].

Physical interactions of Galpha49B

• G beta gamma dimers bind G alpha subunits and anchor them to the membrane for presentation to the receptor [13].
• The predicted sequence of Pins contained tetratrico-peptide repeats (TPRs) and motifs implicated in binding Galpha proteins [15].

Other interactions of Galpha49B

• Light-dependent subcellular translocation of Gqalpha in Drosophila photoreceptors is facilitated by the photoreceptor-specific myosin III NINAC [16].
• We propose that DRhoGEF2 uses microtubule dynamics to search for cortical subdomains of receptor-mediated Galpha activation, which in turn causes localized actomyosin contraction associated with morphogenetic movements during development [17].
• The expressed levels of dGqalpha and itpr in the tarsus of poxn70 mutant flies were reduced compared with those of wild-type flies [18].
• Here, we show that the abundance of DUNC-13 in NMJ synaptic boutons is regulated downstream of GalphaS and Galphaq pathways, which have inhibitory and facilitatory roles, respectively [19].
• This set includes Galpha15, Galpha16, Galphaq, and chimeric Galphaq proteins with the last few amino acids of either Galphai2 (Galphaqi), Galphao (Galphaqo), or Galphaz (Galphaqz) [20].

Analytical, diagnostic and therapeutic context of Galpha49B

• Tissue in situ hybridization detects dgq expression only in the retina and ocellus of the adult head, making it a prime candidate for encoding the Drosophila transducin analog, the G protein required for phototransduction [1].
• We have used the polymerase chain reaction to search for specific G alpha subunits that function primarily during development and not in the adult fly [21].

References