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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 MC3R and GHSR1a results in amplification of MC3R signaling and attenuation of GHSR1a signaling. While it is believed that the pathways involved are not changed, changes in the amplitude of the signals occur. Dimerization with stimulation of MC3R leads to a twofold amplification of MC3R-induced cAMP accumulation (top), while the GHSR1a protomer shows a ligand-dependent as well as ligand-independent 40% reduction in Ca2+ accumulation when dimerized with MC3R (bottom). Amplification of MC3R signaling appears to be dependent on GHSR1a’s constitutive activity.
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Figure 4: Dimerization between MC3R and GHSR1a results in amplification of MC3R signaling and attenuation of GHSR1a signaling. While it is believed that the pathways involved are not changed, changes in the amplitude of the signals occur. Dimerization with stimulation of MC3R leads to a twofold amplification of MC3R-induced cAMP accumulation (top), while the GHSR1a protomer shows a ligand-dependent as well as ligand-independent 40% reduction in Ca2+ accumulation when dimerized with MC3R (bottom). Amplification of MC3R signaling appears to be dependent on GHSR1a’s constitutive activity.

Mentions: Within the arcuate nucleus, most GHSR1a-expressing neurons coexpress MC3R, while a much smaller proportion of MC3R-expressing neurons coexpress GHSR1a (Rediger et al., 2009). Within this overlapping expression, Rediger et al. (2009) have identified MC3R-GHSR1a dimers using FRET. Typical signaling through MC3R involves a Gαs pathway leading to cAMP accumulation. Within this dimer, MC3R-associated cAMP accumulation is increased twofold while GHSR1a constitutive activity and ghrelin-induced activity, as measured by intracellular Ca2+ levels, are reduced by 40% (Fig. 4) (Rediger et al., 2009). Coadministration of α-melanocyte-stimulating hormone (α-MSH) with ghrelin does not affect these changes in signaling (Rediger et al., 2009).


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

Wellman M, Abizaid A - eNeuro (2015)

Dimerization between MC3R and GHSR1a results in amplification of MC3R signaling and attenuation of GHSR1a signaling. While it is believed that the pathways involved are not changed, changes in the amplitude of the signals occur. Dimerization with stimulation of MC3R leads to a twofold amplification of MC3R-induced cAMP accumulation (top), while the GHSR1a protomer shows a ligand-dependent as well as ligand-independent 40% reduction in Ca2+ accumulation when dimerized with MC3R (bottom). Amplification of MC3R signaling appears to be dependent on GHSR1a’s constitutive activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Dimerization between MC3R and GHSR1a results in amplification of MC3R signaling and attenuation of GHSR1a signaling. While it is believed that the pathways involved are not changed, changes in the amplitude of the signals occur. Dimerization with stimulation of MC3R leads to a twofold amplification of MC3R-induced cAMP accumulation (top), while the GHSR1a protomer shows a ligand-dependent as well as ligand-independent 40% reduction in Ca2+ accumulation when dimerized with MC3R (bottom). Amplification of MC3R signaling appears to be dependent on GHSR1a’s constitutive activity.
Mentions: Within the arcuate nucleus, most GHSR1a-expressing neurons coexpress MC3R, while a much smaller proportion of MC3R-expressing neurons coexpress GHSR1a (Rediger et al., 2009). Within this overlapping expression, Rediger et al. (2009) have identified MC3R-GHSR1a dimers using FRET. Typical signaling through MC3R involves a Gαs pathway leading to cAMP accumulation. Within this dimer, MC3R-associated cAMP accumulation is increased twofold while GHSR1a constitutive activity and ghrelin-induced activity, as measured by intracellular Ca2+ levels, are reduced by 40% (Fig. 4) (Rediger et al., 2009). Coadministration of α-melanocyte-stimulating hormone (α-MSH) with ghrelin does not affect these changes in signaling (Rediger et al., 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