Growth hormone secretagogue receptor(GHS-R), also known as ghrelin receptor, is a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
that binds growth hormone secretagogues (GHSs), such as
ghrelin
Ghrelin (; or lenomorelin, INN) is a hormone produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highe ...
, the "hunger hormone".
The role of GHS-R is thought to be in regulating energy homeostasis and body weight.
In the brain, they are most highly expressed in the
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
, specifically the
ventromedial nucleus
The ventromedial nucleus of the hypothalamus (VMN, also sometimes referred to as the ventromedial hypothalamus, VMH) is a Nucleus (neuroanatomy), nucleus of the hypothalamus. "The ventromedial hypothalamus (VMH) is a distinct morphological nucleu ...
and
arcuate nucleus
The arcuate nucleus of the hypothalamus (also known as ARH, ARC, or infundibular nucleus) is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several ...
. GSH-Rs are also expressed in other areas of the brain, including the
ventral tegmental area
The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is the ...
,
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
, and
substantia nigra
The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
.
Outside the central nervous system, too, GSH-Rs are also found in the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, in
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, and even in the
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
.
Structure
Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for ghrelin; however, it may function to attenuate activity of isoform 1a.
GHS-R1a falls into
G-protein-coupled receptor (GPCR) family. Previous studies have shown that GPCRs can form
heterodimers
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
, or functional receptor pairs with other types of G-protein coupled receptors (GPCRs). Various studies suggest that GHS-R1a specifically forms
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
s with the following hormone and neurotransmitter receptors:
somatostatin receptor 5
Somatostatin receptor type 5 is a protein that in humans is encoded by the ''SSTR5'' gene.
Somatostatin acts at many sites to inhibit the release of many hormones and other secretory proteins. The biological effects of somatostatin are probably ...
,
dopamine receptor type 2 (DRD2),
melanocortin-3 receptor (MC3R), and
serotonin receptor type 2C (5-HT2c receptor).
See "Function" section below for details on the purported functions of these heterodimers.
Function
Growth hormone release
The binding of ghrelin to GHS-R1a in pituitary cells stimulates the secretion of
growth hormone (GH) by the
pituitary gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
.
Constitutive activity
One important feature of GHS-R1a is that there is still some activity in the receptor even when it is not actively being stimulated. This is called
constitutive activity
In biochemistry and pharmacology, receptors are chemical structures, composed of protein, that receive and transduce signals that may be integrated into biological systems. These signals are typically chemical messengers which bind to a recepto ...
, and it means that the receptor is always "on," unless acted on by an
inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
. This constitutive activity seems to provide a tonic signal required for the development of normal height, probably through an effect on the GH axis. In fact, some genetic variations, or
single nucleotide polymorphisms (SNPs), in growth hormone secretagogue receptor, have been found to be associated with hereditary obesity and others with hereditary short stature.
It was also found that, when GHS-R1A constitutive activity, was diminished, there were decreased levels of hunger-inducing hormone
neuropeptide Y (NPY) as well as in food intake and body weight.
Intracellular signaling mechanisms
When growth hormone secretagogue receptor is activated, a variety of different intracellular signaling cascades can result, depending on the cell type in which the receptor is expressed. These intracellular signaling cascades include
mitogen-activated protein kinase (MAPK)),
protein kinase A (PKA),
protein kinase B (PKB), also known as
AKT
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transc ...
), and
AMP Activated Protein Kinase (AMPK) cascades.
Behavioral reinforcement of food intake
It is well-characterized that activating the growth hormone secretagogue receptor with ghrelin induces an
orexigenic
An orexigenic, or appetite stimulant, is a drug, hormone, or compound that increases appetite and may induce hyperphagia. This can be a medication or a naturally occurring neuropeptide hormone, such as ghrelin, orexin or neuropeptide Y, which incre ...
state, or general feeling of hunger.
However, ghrelin may also play a role in behavioral reinforcement. Studies in animal models, found that food intake increased when ghrelin was specifically administered to just the ventral tegmental area (VTA), a brain area that uses dopamine signaling to reinforce behavior.
In fact, the more ghrelin administered, the more food the rodent consumed.
This is called a
dose-dependent effect. Building on this, it was found that there are growth hormone secretagogue receptors in the VTA and that ghrelin acts on the VTA through these receptors.
Current studies, furthermore, suggest that the VTA may contain dimers of GHS-R1a and dopamine receptor type 2 (DRD2). If these two receptors do indeed form dimers, this would somehow link ghrelin signaling to dopaminergic signaling.
Enhancement of learning and memory
The growth hormone secretagogue receptor may also be linked to learning and memory. First of all, the receptor is found in the
hippocampus
The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
, the brain region responsible for long-term memory.
Second, it was found that specifically activating the receptor in just the hippocampus increased both
long-term potentiation
In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
(LTP) and
dendritic spine
A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical si ...
density, two cellular phenomena thought to be involved in learning.
Third, short-term calorie restriction, defined as a 30% reduction in caloric intake for two weeks, which naturally increases ghrelin levels and thus activates the receptor, was found to increase both performance on
spatial learning
In cognitive psychology and neuroscience, spatial memory is a form of memory responsible for the recording and recovery of information needed to plan a course to a location and to recall the location of an object or the occurrence of an event. Sp ...
tasks as well as
neurogenesis in the adult hippocampus.
Selective ligands
A range of selective ligands for the GHS-R receptor are now available and are being developed for several clinical applications. GHS-R agonists have appetite-stimulating and growth hormone-releasing effects, and are likely to be useful for the treatment of muscle wasting and frailty associated with old-age and degenerative diseases. On the other hand, GHS-R antagonists have
anorectic
An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic.
The term is (from the Greek ''ἀν-'' (an-) = "without" a ...
effects and are likely to be useful for the treatment of
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
.
Agonists
*
Adenosine
Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
*
Alexamorelin
*
Anamorelin
*
Capromorelin
*
CP-464709
*
Cortistatin-14
*
Examorelin (hexarelin)
*
Ghrelin (lenomorelin)
*
GHRP-1
*
GHRP-3
*
GHRP-4
*
GHRP-5
*
GHRP-6
Growth hormone-releasing peptide 6 (GHRP-6) (developmental code name SKF-110679), also known as growth hormone-releasing hexapeptide, is one of several synthetic met-enkephalin analogues that include unnatural D-amino acids, were developed for ...
*
Ibutamoren (MK-677)
*
Ipamorelin
Ipamorelin ( INN) (developmental code name NNC 26-0161) is a peptide selective agonist of the ghrelin/growth hormone secretagogue receptor (GHS) and a growth hormone secretagogue. It is a pentapeptide with the amino acid sequence Aib-His-D-2-Na ...
*
L-692,585
*
LY-426410
*
LY-444711
*
Macimorelin
*
Pralmorelin (GHRP-2)
*
Relamorelin
*
SM-130,686
*
Tabimorelin
*
Ulimorelin
Antagonists
*
A-778,193
*
PF-5190457
References
Further reading
*
External links
*
*
Ghrelinat
Colorado State University
Colorado State University (Colorado State or CSU) is a public land-grant research university in Fort Collins, Colorado. It is the flagship university of the Colorado State University System. Colorado State University is classified among "R1: ...
{{GH/IGF-1 axis signaling modulators
G protein-coupled receptors