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Growth Hormone Secretagogue Receptor Dimers: A New Pharmacological Target(1,2,3).

Wellman M, Abizaid A - eNeuro (2015)

Bottom Line: While in some cases the ghrelin peptide is not required for these modifications to occur, in others, the presence is necessary for these changes to take effect.These heterodimers demonstrate the broad array of roles and complexity of the ghrelin system.By better understanding how these dimers work, it is hoped that improved treatments for a variety of disorders, including Parkinson's disease, schizophrenia, addiction, obesity, diabetes, and more, can be devised.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Carleton University , Ottawa, Ontario, Canada , K1S 5B6.

ABSTRACT
The growth hormone secretagogue receptor (GHSR1a), the target of the ghrelin peptide, is widely distributed throughout the brain, and, while studies have often reported very low or absent levels of central ghrelin, it is now known that GHSR1a, even in the absence of a natural ligand, has physiological roles. Not only do these roles originate from the receptor's constitutive activity, but recent data indicate that GHSR1a dimerizes with a wide array of other receptors. These include the dopamine 1 receptor (D1R), the dopamine 2 receptor (D2R), the melanocortin-3 receptor (MC3R), the serotonin 2C receptor (5-HT2C), and possibly the cannabinoid type 1 receptor (CB1). Within these dimers, signaling of the protomers involved are modified through facilitation, inhibition, and even modification of signaling pathways resulting in physiological consequences not seen in the absence of these dimers. While in some cases the ghrelin peptide is not required for these modifications to occur, in others, the presence is necessary for these changes to take effect. These heterodimers demonstrate the broad array of roles and complexity of the ghrelin system. By better understanding how these dimers work, it is hoped that improved treatments for a variety of disorders, including Parkinson's disease, schizophrenia, addiction, obesity, diabetes, and more, can be devised. In this review, we examine the current state of knowledge surrounding GHSR heterodimers, and how we can apply this knowledge to various pharmacological treatments.

No MeSH data available.


Related in: MedlinePlus

Dimerization between D2R and GHSR1a. Proposed signaling through D2R involves coupling to a Gi pathway, which typically does not involve intracellular Ca2+ accumulation from the endoplasmic reticulum. Dimerization with GHSR1a, in the absence of a ghrelin ligand leads to a PLC-dependent accumulation of Ca2+. D2R’s Gβγ subunit acts to stimulate PLC activity, and αi coupling by D2R is also required for Ca2+ accumulation. In contrast, Gαq activity associated with GHSR1a is not required for D2R-induced Ca2+ accumulation. It is believed that the D2R-GHSR1a dimer is responsible for the anorectic effects of D2R agonists such as cabergoline.
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Figure 3: Dimerization between D2R and GHSR1a. Proposed signaling through D2R involves coupling to a Gi pathway, which typically does not involve intracellular Ca2+ accumulation from the endoplasmic reticulum. Dimerization with GHSR1a, in the absence of a ghrelin ligand leads to a PLC-dependent accumulation of Ca2+. D2R’s Gβγ subunit acts to stimulate PLC activity, and αi coupling by D2R is also required for Ca2+ accumulation. In contrast, Gαq activity associated with GHSR1a is not required for D2R-induced Ca2+ accumulation. It is believed that the D2R-GHSR1a dimer is responsible for the anorectic effects of D2R agonists such as cabergoline.

Mentions: Using a variety of inhibitors of second messenger signaling molecules, Kern and colleagues (2012) identified the pathway responsible for D2R-induced Ca2+ mobilization when dimerized with GHSR1a. This pathway included PLC-dependent activation through Gαi coupling, ultimately leading to release of Ca2+ from the endoplasmic reticulum via IP3 receptors (Fig. 3). Interestingly, by similarly inhibiting specific pathway components, it was shown that this signaling was dependent on Gβγ subunits derived from D2R’s Gαi/o, stimulating PLC activity. Furthermore, dimerization of D2R with a GHSR1a mutant lacking constitutive activity still displayed dopamine-induced Ca2+ mobilization, albeit considerably reduced, while two constitutively active mutants were absent in Ca2+ mobilization, suggesting that Ca2+ mobilization is independent of GHSR1a constitutive activity. In addition, inhibiting GHSR1a’s Gαq using siRNA did not result in loss of dopamine-induced Ca2+ mobilization, but did significantly reduce ghrelin-induced Ca2+ mobilization. Overall, evidence suggests that GHSR1a’s constitutive activity is not required for the alteration in D2R-mediated signaling. Perhaps the most striking results obtained by Kern et al. are the behavioral data examining the interaction between D2R and the GHSR1a in mice (Vucetic and Reyes, 2010; Kern et al., 2012). Cabergoline, a D2R-selective agonist, produces a dose-dependent suppression of food intake in wild-type mice and in ghrelin KO mice, but has no effect on food intake in GHSR KO mice (Kern et al., 2012). These data clearly show that the anorexigenic effects of cabergoline depend on GHSR1a and not on ghrelin, providing more evidence that GHSR1a has a central role even in the absence of the ghrelin peptide.


Growth Hormone Secretagogue Receptor Dimers: A New Pharmacological Target(1,2,3).

Wellman M, Abizaid A - eNeuro (2015)

Dimerization between D2R and GHSR1a. Proposed signaling through D2R involves coupling to a Gi pathway, which typically does not involve intracellular Ca2+ accumulation from the endoplasmic reticulum. Dimerization with GHSR1a, in the absence of a ghrelin ligand leads to a PLC-dependent accumulation of Ca2+. D2R’s Gβγ subunit acts to stimulate PLC activity, and αi coupling by D2R is also required for Ca2+ accumulation. In contrast, Gαq activity associated with GHSR1a is not required for D2R-induced Ca2+ accumulation. It is believed that the D2R-GHSR1a dimer is responsible for the anorectic effects of D2R agonists such as cabergoline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4596092&req=5

Figure 3: Dimerization between D2R and GHSR1a. Proposed signaling through D2R involves coupling to a Gi pathway, which typically does not involve intracellular Ca2+ accumulation from the endoplasmic reticulum. Dimerization with GHSR1a, in the absence of a ghrelin ligand leads to a PLC-dependent accumulation of Ca2+. D2R’s Gβγ subunit acts to stimulate PLC activity, and αi coupling by D2R is also required for Ca2+ accumulation. In contrast, Gαq activity associated with GHSR1a is not required for D2R-induced Ca2+ accumulation. It is believed that the D2R-GHSR1a dimer is responsible for the anorectic effects of D2R agonists such as cabergoline.
Mentions: Using a variety of inhibitors of second messenger signaling molecules, Kern and colleagues (2012) identified the pathway responsible for D2R-induced Ca2+ mobilization when dimerized with GHSR1a. This pathway included PLC-dependent activation through Gαi coupling, ultimately leading to release of Ca2+ from the endoplasmic reticulum via IP3 receptors (Fig. 3). Interestingly, by similarly inhibiting specific pathway components, it was shown that this signaling was dependent on Gβγ subunits derived from D2R’s Gαi/o, stimulating PLC activity. Furthermore, dimerization of D2R with a GHSR1a mutant lacking constitutive activity still displayed dopamine-induced Ca2+ mobilization, albeit considerably reduced, while two constitutively active mutants were absent in Ca2+ mobilization, suggesting that Ca2+ mobilization is independent of GHSR1a constitutive activity. In addition, inhibiting GHSR1a’s Gαq using siRNA did not result in loss of dopamine-induced Ca2+ mobilization, but did significantly reduce ghrelin-induced Ca2+ mobilization. Overall, evidence suggests that GHSR1a’s constitutive activity is not required for the alteration in D2R-mediated signaling. Perhaps the most striking results obtained by Kern et al. are the behavioral data examining the interaction between D2R and the GHSR1a in mice (Vucetic and Reyes, 2010; Kern et al., 2012). Cabergoline, a D2R-selective agonist, produces a dose-dependent suppression of food intake in wild-type mice and in ghrelin KO mice, but has no effect on food intake in GHSR KO mice (Kern et al., 2012). These data clearly show that the anorexigenic effects of cabergoline depend on GHSR1a and not on ghrelin, providing more evidence that GHSR1a has a central role even in the absence of the ghrelin peptide.

Bottom Line: While in some cases the ghrelin peptide is not required for these modifications to occur, in others, the presence is necessary for these changes to take effect.These heterodimers demonstrate the broad array of roles and complexity of the ghrelin system.By better understanding how these dimers work, it is hoped that improved treatments for a variety of disorders, including Parkinson's disease, schizophrenia, addiction, obesity, diabetes, and more, can be devised.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neuroscience, Carleton University , Ottawa, Ontario, Canada , K1S 5B6.

ABSTRACT
The growth hormone secretagogue receptor (GHSR1a), the target of the ghrelin peptide, is widely distributed throughout the brain, and, while studies have often reported very low or absent levels of central ghrelin, it is now known that GHSR1a, even in the absence of a natural ligand, has physiological roles. Not only do these roles originate from the receptor's constitutive activity, but recent data indicate that GHSR1a dimerizes with a wide array of other receptors. These include the dopamine 1 receptor (D1R), the dopamine 2 receptor (D2R), the melanocortin-3 receptor (MC3R), the serotonin 2C receptor (5-HT2C), and possibly the cannabinoid type 1 receptor (CB1). Within these dimers, signaling of the protomers involved are modified through facilitation, inhibition, and even modification of signaling pathways resulting in physiological consequences not seen in the absence of these dimers. While in some cases the ghrelin peptide is not required for these modifications to occur, in others, the presence is necessary for these changes to take effect. These heterodimers demonstrate the broad array of roles and complexity of the ghrelin system. By better understanding how these dimers work, it is hoped that improved treatments for a variety of disorders, including Parkinson's disease, schizophrenia, addiction, obesity, diabetes, and more, can be devised. In this review, we examine the current state of knowledge surrounding GHSR heterodimers, and how we can apply this knowledge to various pharmacological treatments.

No MeSH data available.


Related in: MedlinePlus