The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). Decreased production of cAMP from ATP results in decreased activity of cAMP-dependent protein kinases. Other functions of G alpha (i) includes activation of the protein tyrosine kinase c-Src (Ma Y C et al. 2000). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (i) (Soundararajan M et al. 2008).
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The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha.
GPR183 (originally called EBI2) binds the oxysterol 7alpha,25-dihydroxycholesterol (7a,25-OHC) (Hannedouche et al. 2011, Liu et al. 2011). GPR183 is believed to played a key role in regulating B cell migration and responses (Gatto et al. 2009, Pereira et al. 2009, Yi et al. 2012, Sun & Liu 2015). It signals via Gi (Rosenkilde et al. 2006).
Opioids are chemical substances similar to opiates, the active substances found in opium (morphine, codeine etc.). Opioid action is mediated by the receptors for endogenous opioids; peptides such as the enkephalins, the endorphins or the dynorphins. Opioids possess powerful analgesic and sedative effects, and are widely used as pain-killers. Their main side-effect is the rapid establishment of a strong addiction. Opioids receptors are G-protein coupled receptors (GPCR). There are four classes of receptors: mu (MOR), kappa (KOR) and delta (DOR), and the nociceptin receptor (NOP).
Paper describes 'full-length' prosaposin but methods indicate a 'C-teminal fragment' so the actual fragment represented by this full-length prosaposin is unclear.
Visual phototransduction is the process by which photon absorption by visual pigment molecules in photoreceptor cells is converted to an electrical cellular response. The events in this process are photochemical, biochemical and electrophysiological and are highly conserved across many species. This process occurs in two types of photoreceptors in the retina, rods and cones. Each type consists of two parts, the outer segment which detects a photon signal and the inner segment which contains the necessary machinery for cell metabolism. Each type of cell functions differently. Rods are very light sensitive but their flash response is slow so they work best in twilight conditions but are not good at detecting objects moving quickly. Cones are less light-sensitive and have a fast flash response so they work best in daylight conditions and are better at detecting fast moving objects than rods.
The visual pigment consists of a chromophore (11-cis-retinal, 11cRAL, A1) covalently attached to a GPCR opsin family member. The linkage is via a Schiff base forming retinylidene protein. Upon photon absorption, 11cRAL isomerises to all-trans retinal (atRAL), changing the conformation of opsin to an activated form which can activate the regulatory G protein transducin (Gt). The alpha subunit of Gt activates phosphodiesterase which hydrolyses cGMP to 5'-GMP. As high level of cGMP keep cGMP-gated sodium channels open, the lowering of cGMP levels closes these channels which causes hyperpolarization of the cell and subsequently, closure of voltage-gated calcium channels. As calcium levels drop, the level of the neurotransmitter glutamate also drops causing depolarization of the cell. This effectively relays the light signal to postsynaptic neurons as electrical signal (Burns & Pugh 2010, Korenbrot 2012, Pugh & Lamb 1993).
11cRAL cannot be synthesised in vertebrates. Vitamin A from many dietary sources is the precursor for 11cRAL. It is taken from food in the form of esters such as retinyl acetate or palmitate or one of four caretenoids (alpha-carotene, beta-carotene, gamma-carotene and beta-cryptoxanthin). Retinoids are transported from the gut to be stored in liver, until required by target organs such as the eye (Harrison & Hussain 2001, Harrison 2005). In the eye, in the form 11cRAL, it is used in the retinoid (visual) cycle to initiate phototransduction and for visual pigment regeneration to ready the photoreceptor for the next phototransduction event (von Lintig 2012, Blomhoff & Blomhoff 2006, von Lintig et al. 2010, D'Ambrosio et al. 2011, Wang & Kefalov 2011, Kefalov 2012, Wolf 2004).
The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein.
This event is negatively regulated by some Activators of G protein signaling (AGS) proteins, a class of proteins identified in yeast functional screens for proteins able to activate G protein signaling in the absence of a G protein–coupled receptor (GPCR) (Cismowski et al. 1999, Takesono et al. 1999). AGS proteins contain G protein regulatory (GPR) motifs (also referred to as the GoLoco motif) that bind and stabilize the Galpha subunit in its GDP-bound conformation (Mochizuki et al. 1996, Peterson et al. 2000, Cao et al. 2004, Blumer & Lanier 2014). Some RGS proteins similarly bind to Galpha preventing the exchange of GDP for GTP (Soundararajan et al. 2008).
The activation of adenylyl (adenylate) cyclase (AC) results in the production of adenosine-3',5'-monophosphate i.e. cyclic AMP. Humans have 9 genes encoding membrane-associated AC and one encoding a soluble AC. Two of the classes of heterotrimeric G-proteins are named according to their effect on AC; Gs stimulates all membrane-bound ACs (the s in Gs denotes AC stimulatory); the Gi class inhibits some AC isoforms, particularly 5 and 6. Beta-gamma subunits of heterotrimeric G-proteins can also regulate AC. Ca2+/Calmodulin activates some AC isoforms (1, 8 and 3) but is inhibitory to others (5 and 6).
G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells.
When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region (Kleuss et al. 1994).
Transducin (Gt) is a heterotrimeric G protein encoded by GNAT genes and is naturally expressed in vertebrate retina rods and cones. There are two types, alpha-1 chain (expressed in rods by GNAT1) (Lerea CL et al, 1989) and alpha-2 chain (expressed in cones by GNAT2) (Morris TA and Fong SL, 1993). Stimulated opsins can act as GEFs for G (t) alpha subunits by replacing GDP with GTP. Consequently, the G (t) alpha subunit is activated and results in the "vertebrate phototransduction cascade" (Chen CK, 2005). Cyclic GMP Phosphodiesterase is activated which lowers cGMP levels (an intracellular second messenger molecule). Lower cGMP levels can then lead to the closure of cGMP-regulated Na+ and Ca2+ ion channels and a hyperpolarized membrane potential.
The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (i) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
Many unrelated GPCRs couple with the Gi G-protein subtype. The G-alpha (i) subunit inhibits the production of cAMP from ATP. In turn, this results in decreased activity of cAMP-dependent protein kinase. There are 8 types of G-alpha (i) known to date:G(i)1, G(i)2, G(i)3, G(i)o, G(i)z, G(i)gust (gustducin) and two G(i)t (retinal transducin) (Downes GB and Gautam N, 1999). Once GDP is exchanged for GTP on the alpha subunit, it dissociates from the G-beta-gamma subunit.
The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (i) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (i):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates.
Transducin (Gt) is a heterotrimeric G protein encoded by GNAT genes and is naturally expressed in vertebrate retina rods and cones. There are two types, alpha-1 chain (expressed in rods by GNAT1) (Lerea CL et al, 1989) and alpha-2 chain (expressed in cones by GNAT2) (Morris TA and Fong SL, 1993). Photon activated-opsins can bind to G(t) alpha subunits and stimulate them. Activation of the G(t) alpha subunit results in the "vertebrate phototransduction cascade" (Chen CK, 2005). Cyclic GMP Phosphodiesterase is activated which lowers cGMP levels (an intracellular second messenger molecule). Lower cGMP levels can then lead to the closure of cGMP-regulated Na+ and Ca2+ ion channels and a hyperpolarized membrane potential.
Transducin (Gt) is a heterotrimeric G protein encoded by GNAT genes and is naturally expressed in vertebrate retina rods and cones. There are two types, alpha-1 chain (expressed in rods by GNAT1) (Lerea CL et al, 1989) and alpha-2 chain (expressed in cones by GNAT2) (Morris TA and Fong SL, 1993). Stimulated opsins can bind to and act as GEFs for G (t) alpha subunits thereby replacing the GDP with GTP. Subsequently, activated G (t) alpha proteins dissociate from the complex. Activation of the G (t) alpha subunit results in the "vertebrate phototransduction cascade" (Chen CK, 2005). Cyclic GMP Phosphodiesterase is activated which lowers cGMP levels (an intracellular second messenger molecule). Lower cGMP levels can then lead to the closure of cGMP-regulated Na+ and Ca2+ ion channels and a hyperpolarized membrane potential.
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DataNodes
(s):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclaseG-protein Gi
(inactive)complexes that activate Gi:Heterotrimeric G-protein Gi
(active)complexes that activate Gi:Heterotrimeric G-protein Gi
(inactive)complexes that
activate GiThe visual pigment consists of a chromophore (11-cis-retinal, 11cRAL, A1) covalently attached to a GPCR opsin family member. The linkage is via a Schiff base forming retinylidene protein. Upon photon absorption, 11cRAL isomerises to all-trans retinal (atRAL), changing the conformation of opsin to an activated form which can activate the regulatory G protein transducin (Gt). The alpha subunit of Gt activates phosphodiesterase which hydrolyses cGMP to 5'-GMP. As high level of cGMP keep cGMP-gated sodium channels open, the lowering of cGMP levels closes these channels which causes hyperpolarization of the cell and subsequently, closure of voltage-gated calcium channels. As calcium levels drop, the level of the neurotransmitter glutamate also drops causing depolarization of the cell. This effectively relays the light signal to postsynaptic neurons as electrical signal (Burns & Pugh 2010, Korenbrot 2012, Pugh & Lamb 1993).
11cRAL cannot be synthesised in vertebrates. Vitamin A from many dietary sources is the precursor for 11cRAL. It is taken from food in the form of esters such as retinyl acetate or palmitate or one of four caretenoids (alpha-carotene, beta-carotene, gamma-carotene and beta-cryptoxanthin). Retinoids are transported from the gut to be stored in liver, until required by target organs such as the eye (Harrison & Hussain 2001, Harrison 2005). In the eye, in the form 11cRAL, it is used in the retinoid (visual) cycle to initiate phototransduction and for visual pigment regeneration to ready the photoreceptor for the next phototransduction event (von Lintig 2012, Blomhoff & Blomhoff 2006, von Lintig et al. 2010, D'Ambrosio et al. 2011, Wang & Kefalov 2011, Kefalov 2012, Wolf 2004).
Annotated Interactions
(s):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclaseG-protein Gi
(inactive)G-protein Gi
(inactive)complexes that activate Gi:Heterotrimeric G-protein Gi
(active)complexes that activate Gi:Heterotrimeric G-protein Gi
(active)complexes that activate Gi:Heterotrimeric G-protein Gi
(inactive)complexes that activate Gi:Heterotrimeric G-protein Gi
(inactive)complexes that activate Gi:Heterotrimeric G-protein Gi
(inactive)complexes that
activate Gi