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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

Fluorescence resonance energy transfer. In this FRET example, cyan fluorescent protein (CFP) acts as the donor and yellow fluorescent protein (YFP) as the acceptor. When the two fluorophores are separated by a considerable distance, exposing the sample to light with the excitation frequency for CFP results in an emission spectrum corresponding to CFP only, with no contribution from the acceptor (top). When the two fluorophores are nearby (typically in the range of 10 to 100 Å), exposing the sample to the same light results in a nonradiative energy transfer from CFP to the nearby YFP acceptor, causing YFP to emit at its emission frequency (bottom). At the same time, due to the transfer of energy, emission from CFP is considerably reduced. Detection of YFP emission indicates that fluorescence resonance energy transfer has occurred between the two fluorophores as a result of their close proximity. By fusing these fluorophores to the receptors of interest, dimerization can be implied if fluorescence resonance energy transfer is observed.
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Figure 1: Fluorescence resonance energy transfer. In this FRET example, cyan fluorescent protein (CFP) acts as the donor and yellow fluorescent protein (YFP) as the acceptor. When the two fluorophores are separated by a considerable distance, exposing the sample to light with the excitation frequency for CFP results in an emission spectrum corresponding to CFP only, with no contribution from the acceptor (top). When the two fluorophores are nearby (typically in the range of 10 to 100 Å), exposing the sample to the same light results in a nonradiative energy transfer from CFP to the nearby YFP acceptor, causing YFP to emit at its emission frequency (bottom). At the same time, due to the transfer of energy, emission from CFP is considerably reduced. Detection of YFP emission indicates that fluorescence resonance energy transfer has occurred between the two fluorophores as a result of their close proximity. By fusing these fluorophores to the receptors of interest, dimerization can be implied if fluorescence resonance energy transfer is observed.

Mentions: A technique that avoids many of the problems of coimmunoprecipitation is resonance energy transfer (RET) and its derivative techniques (Fig. 1). Perhaps one of its most powerful advantages is its ability to measure dimerization in real-time in living cells. While there are many techniques related to RET, they all involve the nonradiative transfer of energy (on the nanoscale range) between a donor and a nearby acceptor, which have been fused to the two receptors of interest. This transfer is measured by examining the emission of energy from the acceptor after it has accepted the transfer from the donor. For example, in the case of fluorescence resonance energy transfer (FRET), the donor is excited by light of a certain wavelength. If the donor is in close proximity to the acceptor, this energy is transferred and then emitted at a characteristic wavelength by the acceptor, which can be measured by scanning spectroscopy, a microplate reader, or microscopy. In the case of bioluminescence resonance energy transfer (BRET), a donor such as the enzyme Renilla luciferase is used.


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

Wellman M, Abizaid A - eNeuro (2015)

Fluorescence resonance energy transfer. In this FRET example, cyan fluorescent protein (CFP) acts as the donor and yellow fluorescent protein (YFP) as the acceptor. When the two fluorophores are separated by a considerable distance, exposing the sample to light with the excitation frequency for CFP results in an emission spectrum corresponding to CFP only, with no contribution from the acceptor (top). When the two fluorophores are nearby (typically in the range of 10 to 100 Å), exposing the sample to the same light results in a nonradiative energy transfer from CFP to the nearby YFP acceptor, causing YFP to emit at its emission frequency (bottom). At the same time, due to the transfer of energy, emission from CFP is considerably reduced. Detection of YFP emission indicates that fluorescence resonance energy transfer has occurred between the two fluorophores as a result of their close proximity. By fusing these fluorophores to the receptors of interest, dimerization can be implied if fluorescence resonance energy transfer is observed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Fluorescence resonance energy transfer. In this FRET example, cyan fluorescent protein (CFP) acts as the donor and yellow fluorescent protein (YFP) as the acceptor. When the two fluorophores are separated by a considerable distance, exposing the sample to light with the excitation frequency for CFP results in an emission spectrum corresponding to CFP only, with no contribution from the acceptor (top). When the two fluorophores are nearby (typically in the range of 10 to 100 Å), exposing the sample to the same light results in a nonradiative energy transfer from CFP to the nearby YFP acceptor, causing YFP to emit at its emission frequency (bottom). At the same time, due to the transfer of energy, emission from CFP is considerably reduced. Detection of YFP emission indicates that fluorescence resonance energy transfer has occurred between the two fluorophores as a result of their close proximity. By fusing these fluorophores to the receptors of interest, dimerization can be implied if fluorescence resonance energy transfer is observed.
Mentions: A technique that avoids many of the problems of coimmunoprecipitation is resonance energy transfer (RET) and its derivative techniques (Fig. 1). Perhaps one of its most powerful advantages is its ability to measure dimerization in real-time in living cells. While there are many techniques related to RET, they all involve the nonradiative transfer of energy (on the nanoscale range) between a donor and a nearby acceptor, which have been fused to the two receptors of interest. This transfer is measured by examining the emission of energy from the acceptor after it has accepted the transfer from the donor. For example, in the case of fluorescence resonance energy transfer (FRET), the donor is excited by light of a certain wavelength. If the donor is in close proximity to the acceptor, this energy is transferred and then emitted at a characteristic wavelength by the acceptor, which can be measured by scanning spectroscopy, a microplate reader, or microscopy. In the case of bioluminescence resonance energy transfer (BRET), a donor such as the enzyme Renilla luciferase is used.

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