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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 5-HT2C and GHSR1a. When dimerized with 5-HT2C. GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. While changes in serotonergic signaling associated with the dimer through 5-HT2C have not yet been observed, cross-desensitization, cross-sensitization, and cointernalization do occur.
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Figure 5: Dimerization between 5-HT2C and GHSR1a. When dimerized with 5-HT2C. GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. While changes in serotonergic signaling associated with the dimer through 5-HT2C have not yet been observed, cross-desensitization, cross-sensitization, and cointernalization do occur.

Mentions: Recently, the 5-HT2C receptor has also been identified as a dimerization partner of GHSR1a (Fig. 5). Like the GHSR1a, the 5-HT2C serotonin receptor signals through a Gαq pathway, leading to Ca2+ accumulation (Schellekens et al., 2013). Paradoxically, stimulation of the 5-HT2C receptor results in decreased food intake and adiposity, while mutations to the gene encoding for this receptor result in obesity (Sargent et al., 1997; Martin et al., 1998; Nonogaki et al., 1998; Somerville et al., 2007; Garfield and Heisler, 2009). One proposed mechanism of action is that stimulation of 5-HT2C receptors in pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus leads to increased release of α-MSH (Garfield and Heisler, 2009).


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

Wellman M, Abizaid A - eNeuro (2015)

Dimerization between 5-HT2C and GHSR1a. When dimerized with 5-HT2C. GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. While changes in serotonergic signaling associated with the dimer through 5-HT2C have not yet been observed, cross-desensitization, cross-sensitization, and cointernalization do occur.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Dimerization between 5-HT2C and GHSR1a. When dimerized with 5-HT2C. GHSR1a displays a 65% reduction in ghrelin-induced Ca2+ accumulation, with this effect not requiring the presence of a 5-HT2C ligand. While changes in serotonergic signaling associated with the dimer through 5-HT2C have not yet been observed, cross-desensitization, cross-sensitization, and cointernalization do occur.
Mentions: Recently, the 5-HT2C receptor has also been identified as a dimerization partner of GHSR1a (Fig. 5). Like the GHSR1a, the 5-HT2C serotonin receptor signals through a Gαq pathway, leading to Ca2+ accumulation (Schellekens et al., 2013). Paradoxically, stimulation of the 5-HT2C receptor results in decreased food intake and adiposity, while mutations to the gene encoding for this receptor result in obesity (Sargent et al., 1997; Martin et al., 1998; Nonogaki et al., 1998; Somerville et al., 2007; Garfield and Heisler, 2009). One proposed mechanism of action is that stimulation of 5-HT2C receptors in pro-opiomelanocortin (POMC) neurons within the arcuate nucleus of the hypothalamus leads to increased release of α-MSH (Garfield and Heisler, 2009).

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