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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 D1R and GHSR1a. When dimerized with D1R, GHSR1a switches G-protein coupling from Gq/11 to Gi/o. Coadministration of a D1R agonist with a GHSR1a agonist leads to a fourfold amplification of D1R-associated cAMP accumulation. It is believed that the Gβγ subunit associated with GHSR1a adopts a stimulatory role on adenylyl cyclase activity due to the proximity of the αS subunit derived from D1R’s trimeric G-protein.
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Figure 2: Dimerization between D1R and GHSR1a. When dimerized with D1R, GHSR1a switches G-protein coupling from Gq/11 to Gi/o. Coadministration of a D1R agonist with a GHSR1a agonist leads to a fourfold amplification of D1R-associated cAMP accumulation. It is believed that the Gβγ subunit associated with GHSR1a adopts a stimulatory role on adenylyl cyclase activity due to the proximity of the αS subunit derived from D1R’s trimeric G-protein.

Mentions: Coexpression of GHSR1a and D1R has been reported in the cortex, hippocampal structures, substantia nigra, midbrain, and ventral tegmental areas (Jiang et al., 2006). In HEK293 cells expressing D1R and GHSR1a, both a BRET signal and coimmunoprecipitation indicate dimerization between the two receptors (Jiang et al., 2006). As summarized in Figure 2, coadministration of dopamine and ghrelin to these cells show a fourfold amplification of D1R-associated cAMP signaling, with this amplification requiring both receptors and both ligands (Jiang et al., 2006). These data demonstrate dimerization in areas associated with mood, learning, and memory. Interestingly, when ghrelin is administered alone to cells coexpressing D1R and GHSR1a, no increase in cAMP accumulation is observed, while typical levels of Ca2+ accumulation associated with GHSR1a activation occur (Jiang et al., 2006). Despite this, the PKC inhibitor bisindolylmaleimide I (Bis) does not affect cAMP augmentation within the D1/GHSR1a dimer, while pertussis toxin, an inhibitor of the Gi/o pathway, eliminates cAMP augmentation (Jiang et al., 2006). In addition to this, pertussis toxin administration in the absence of ghrelin does not affect dopamine-associated cAMP accumulation, which typically signals through Gαs and Gαolf (Missale et al., 1998; Neve et al., 2004). These data suggest that the synergy between GHSR1a and D1R is due to GHSR1a switching from Gαq/11 coupling to Gαi/o coupling, a G-protein that is not associated with D1R or GHSR1a when expressed alone. In addition to this synergistic effect, cointernalization of D1R-GHSR1a is induced after stimulation by the D1 agonist 6,7-ADTN hydrobromide or GHSR1a agonists (Schellekens et al., 2013). In effect, GHSR1a as well as D1R agonists can terminate the effect of the dimer partner’s natural ligands through cointernalization.


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

Wellman M, Abizaid A - eNeuro (2015)

Dimerization between D1R and GHSR1a. When dimerized with D1R, GHSR1a switches G-protein coupling from Gq/11 to Gi/o. Coadministration of a D1R agonist with a GHSR1a agonist leads to a fourfold amplification of D1R-associated cAMP accumulation. It is believed that the Gβγ subunit associated with GHSR1a adopts a stimulatory role on adenylyl cyclase activity due to the proximity of the αS subunit derived from D1R’s trimeric G-protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Dimerization between D1R and GHSR1a. When dimerized with D1R, GHSR1a switches G-protein coupling from Gq/11 to Gi/o. Coadministration of a D1R agonist with a GHSR1a agonist leads to a fourfold amplification of D1R-associated cAMP accumulation. It is believed that the Gβγ subunit associated with GHSR1a adopts a stimulatory role on adenylyl cyclase activity due to the proximity of the αS subunit derived from D1R’s trimeric G-protein.
Mentions: Coexpression of GHSR1a and D1R has been reported in the cortex, hippocampal structures, substantia nigra, midbrain, and ventral tegmental areas (Jiang et al., 2006). In HEK293 cells expressing D1R and GHSR1a, both a BRET signal and coimmunoprecipitation indicate dimerization between the two receptors (Jiang et al., 2006). As summarized in Figure 2, coadministration of dopamine and ghrelin to these cells show a fourfold amplification of D1R-associated cAMP signaling, with this amplification requiring both receptors and both ligands (Jiang et al., 2006). These data demonstrate dimerization in areas associated with mood, learning, and memory. Interestingly, when ghrelin is administered alone to cells coexpressing D1R and GHSR1a, no increase in cAMP accumulation is observed, while typical levels of Ca2+ accumulation associated with GHSR1a activation occur (Jiang et al., 2006). Despite this, the PKC inhibitor bisindolylmaleimide I (Bis) does not affect cAMP augmentation within the D1/GHSR1a dimer, while pertussis toxin, an inhibitor of the Gi/o pathway, eliminates cAMP augmentation (Jiang et al., 2006). In addition to this, pertussis toxin administration in the absence of ghrelin does not affect dopamine-associated cAMP accumulation, which typically signals through Gαs and Gαolf (Missale et al., 1998; Neve et al., 2004). These data suggest that the synergy between GHSR1a and D1R is due to GHSR1a switching from Gαq/11 coupling to Gαi/o coupling, a G-protein that is not associated with D1R or GHSR1a when expressed alone. In addition to this synergistic effect, cointernalization of D1R-GHSR1a is induced after stimulation by the D1 agonist 6,7-ADTN hydrobromide or GHSR1a agonists (Schellekens et al., 2013). In effect, GHSR1a as well as D1R agonists can terminate the effect of the dimer partner’s natural ligands through cointernalization.

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