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Accessory proteins for heterotrimeric G-proteins in the kidney.

Park F - Front Physiol (2015)

Bottom Line: Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney.In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors.Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center Memphis, TN, USA.

ABSTRACT
Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney. Accessory proteins are being identified as direct binding partners for heterotrimeric G-protein α or βγ subunits to promote more diverse mechanisms by which G-protein signaling is controlled. In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors. Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell. In this review, we will highlight the expression profile, localization and functional importance of these newly identified accessory proteins to control the function of select G-protein subunits under normal and various disease conditions observed in the kidney.

No MeSH data available.


Related in: MedlinePlus

Schematic illustrating the four types of regulation exhibited by accessory proteins on heterotrimeric G-protein subunits. The four main types of regulation mediated by accessory proteins are: (1) GTPase-activating proteins; (2) Guanine exchange factors; (3) Guanine nucleotide dissociation inhibitors; and (4) Gβγ-interacting proteins. Ligand activation promotes a conformational change in the heterotrimeric G-protein associated with the GPCR, which facilitates the switch from GDP to GTP-bound Gα subunits. Subsequently, this leads to the activation of downstream effector systems by Gα-GTP and unbound Gβγ. The Gα subunit has intrinsic GTPase activity to inactivate the signaling output and ultimately, reassociate with its native Gβγ partner. Alternatively, an accessory protein (Acc) functioning as a GAP can interact with Gα-GTP to accelerate the deactivation of the signaling pathway (A). Other accessory proteins can bind to the inactive form of Gα-GDP to either facilitate the activity of Gα by increasing the switch from GDP-to-GTP bound Gα subunits (known as GEFs; B) or bind one or more Gαi/o-GDP subunits to activate other non-canonical signaling pathways (known as GDI; C). The last major type of regulation by accessory proteins is a direct interaction with Gβγ in the presence or absence of the associated Gα subunit (D). As an example, an accessory protein (Acc), such as GRK2/3, can bind with Gβγ to distribute the complex to the plasma membrane and phosphorylate an active GPCR to downregulate its activity, or the physical interaction with Gβγ could disrupt the activated Gβγ-dependent signaling by the unbound dimer. It remains unclear whether accessory proteins complexed with Gβγ promote their own unique signal processing. GPCR, G-protein coupled receptor; αβγ, heterotrimeric G-protein α, β, and γ subunits; GDP, guanine dinucleotide phosphate; GTP, guanine trinucleotide phosphate; Acc, accessory protein.
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Figure 1: Schematic illustrating the four types of regulation exhibited by accessory proteins on heterotrimeric G-protein subunits. The four main types of regulation mediated by accessory proteins are: (1) GTPase-activating proteins; (2) Guanine exchange factors; (3) Guanine nucleotide dissociation inhibitors; and (4) Gβγ-interacting proteins. Ligand activation promotes a conformational change in the heterotrimeric G-protein associated with the GPCR, which facilitates the switch from GDP to GTP-bound Gα subunits. Subsequently, this leads to the activation of downstream effector systems by Gα-GTP and unbound Gβγ. The Gα subunit has intrinsic GTPase activity to inactivate the signaling output and ultimately, reassociate with its native Gβγ partner. Alternatively, an accessory protein (Acc) functioning as a GAP can interact with Gα-GTP to accelerate the deactivation of the signaling pathway (A). Other accessory proteins can bind to the inactive form of Gα-GDP to either facilitate the activity of Gα by increasing the switch from GDP-to-GTP bound Gα subunits (known as GEFs; B) or bind one or more Gαi/o-GDP subunits to activate other non-canonical signaling pathways (known as GDI; C). The last major type of regulation by accessory proteins is a direct interaction with Gβγ in the presence or absence of the associated Gα subunit (D). As an example, an accessory protein (Acc), such as GRK2/3, can bind with Gβγ to distribute the complex to the plasma membrane and phosphorylate an active GPCR to downregulate its activity, or the physical interaction with Gβγ could disrupt the activated Gβγ-dependent signaling by the unbound dimer. It remains unclear whether accessory proteins complexed with Gβγ promote their own unique signal processing. GPCR, G-protein coupled receptor; αβγ, heterotrimeric G-protein α, β, and γ subunits; GDP, guanine dinucleotide phosphate; GTP, guanine trinucleotide phosphate; Acc, accessory protein.

Mentions: In the normal kidney, there are an increasing number of accessory proteins that have been detected using various molecular techniques, but only a few have been described to modulate some aspect of renal tubular function. Figure 1 illustrates the most common modes of action mediated by accessory proteins to control the activation-inactivation cycle of heterotrimeric G-proteins, and are defined in the following categories: (1) GTPase-activating proteins (GAP); (2) guanine exchange factors (GEF); (3) guanine dinucleotide dissociation inhibitors (GDI); and (4) Gβγ-interacting proteins. Figure 2 provides a basic schematic of the protein domain structures for the various accessory proteins.


Accessory proteins for heterotrimeric G-proteins in the kidney.

Park F - Front Physiol (2015)

Schematic illustrating the four types of regulation exhibited by accessory proteins on heterotrimeric G-protein subunits. The four main types of regulation mediated by accessory proteins are: (1) GTPase-activating proteins; (2) Guanine exchange factors; (3) Guanine nucleotide dissociation inhibitors; and (4) Gβγ-interacting proteins. Ligand activation promotes a conformational change in the heterotrimeric G-protein associated with the GPCR, which facilitates the switch from GDP to GTP-bound Gα subunits. Subsequently, this leads to the activation of downstream effector systems by Gα-GTP and unbound Gβγ. The Gα subunit has intrinsic GTPase activity to inactivate the signaling output and ultimately, reassociate with its native Gβγ partner. Alternatively, an accessory protein (Acc) functioning as a GAP can interact with Gα-GTP to accelerate the deactivation of the signaling pathway (A). Other accessory proteins can bind to the inactive form of Gα-GDP to either facilitate the activity of Gα by increasing the switch from GDP-to-GTP bound Gα subunits (known as GEFs; B) or bind one or more Gαi/o-GDP subunits to activate other non-canonical signaling pathways (known as GDI; C). The last major type of regulation by accessory proteins is a direct interaction with Gβγ in the presence or absence of the associated Gα subunit (D). As an example, an accessory protein (Acc), such as GRK2/3, can bind with Gβγ to distribute the complex to the plasma membrane and phosphorylate an active GPCR to downregulate its activity, or the physical interaction with Gβγ could disrupt the activated Gβγ-dependent signaling by the unbound dimer. It remains unclear whether accessory proteins complexed with Gβγ promote their own unique signal processing. GPCR, G-protein coupled receptor; αβγ, heterotrimeric G-protein α, β, and γ subunits; GDP, guanine dinucleotide phosphate; GTP, guanine trinucleotide phosphate; Acc, accessory protein.
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Related In: Results  -  Collection

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Figure 1: Schematic illustrating the four types of regulation exhibited by accessory proteins on heterotrimeric G-protein subunits. The four main types of regulation mediated by accessory proteins are: (1) GTPase-activating proteins; (2) Guanine exchange factors; (3) Guanine nucleotide dissociation inhibitors; and (4) Gβγ-interacting proteins. Ligand activation promotes a conformational change in the heterotrimeric G-protein associated with the GPCR, which facilitates the switch from GDP to GTP-bound Gα subunits. Subsequently, this leads to the activation of downstream effector systems by Gα-GTP and unbound Gβγ. The Gα subunit has intrinsic GTPase activity to inactivate the signaling output and ultimately, reassociate with its native Gβγ partner. Alternatively, an accessory protein (Acc) functioning as a GAP can interact with Gα-GTP to accelerate the deactivation of the signaling pathway (A). Other accessory proteins can bind to the inactive form of Gα-GDP to either facilitate the activity of Gα by increasing the switch from GDP-to-GTP bound Gα subunits (known as GEFs; B) or bind one or more Gαi/o-GDP subunits to activate other non-canonical signaling pathways (known as GDI; C). The last major type of regulation by accessory proteins is a direct interaction with Gβγ in the presence or absence of the associated Gα subunit (D). As an example, an accessory protein (Acc), such as GRK2/3, can bind with Gβγ to distribute the complex to the plasma membrane and phosphorylate an active GPCR to downregulate its activity, or the physical interaction with Gβγ could disrupt the activated Gβγ-dependent signaling by the unbound dimer. It remains unclear whether accessory proteins complexed with Gβγ promote their own unique signal processing. GPCR, G-protein coupled receptor; αβγ, heterotrimeric G-protein α, β, and γ subunits; GDP, guanine dinucleotide phosphate; GTP, guanine trinucleotide phosphate; Acc, accessory protein.
Mentions: In the normal kidney, there are an increasing number of accessory proteins that have been detected using various molecular techniques, but only a few have been described to modulate some aspect of renal tubular function. Figure 1 illustrates the most common modes of action mediated by accessory proteins to control the activation-inactivation cycle of heterotrimeric G-proteins, and are defined in the following categories: (1) GTPase-activating proteins (GAP); (2) guanine exchange factors (GEF); (3) guanine dinucleotide dissociation inhibitors (GDI); and (4) Gβγ-interacting proteins. Figure 2 provides a basic schematic of the protein domain structures for the various accessory proteins.

Bottom Line: Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney.In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors.Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center Memphis, TN, USA.

ABSTRACT
Heterotrimeric G-proteins play a fundamentally important role in regulating signal transduction pathways in the kidney. Accessory proteins are being identified as direct binding partners for heterotrimeric G-protein α or βγ subunits to promote more diverse mechanisms by which G-protein signaling is controlled. In some instances, accessory proteins can modulate the signaling magnitude, localization, and duration following the activation of cell membrane-associated receptors. Alternatively, accessory proteins complexed with their G-protein α or βγ subunits can promote non-canonical models of signaling activity within the cell. In this review, we will highlight the expression profile, localization and functional importance of these newly identified accessory proteins to control the function of select G-protein subunits under normal and various disease conditions observed in the kidney.

No MeSH data available.


Related in: MedlinePlus