Galanin
Encyclopedia
Galanin is a neuropeptide
encoded by the GAL gene
, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.
The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception
, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor. Galanin is linked to a number of diseases including Alzheimer’s disease, epilepsy
as well as depression, eating disorders and cancer
. Galanin appears to have neuroprotective
activity as its biosynthesis is increased 2-10 fold upon axotomy
in the peripheral nervous system
as well as when seizure activity occurs in the brain. It may also promote neurogenesis
.
Galanin is predominantly an inhibitory, hyperpolarizing
neuropeptide and as such inhibits neurotransmitter
release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine
, serotonin
, and norepinephrine
, and also with other neuromodulators such as Neuropeptide Y
, Substance P
, and Vasoactive intestinal peptide
.
, with lower levels in the cortex
and brainstem. Gastrointestinal galanin is most abundant in the duodenum
, with lower concentrations in the stomach, small intestine, and colon.
Galanin is a peptide
consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as preprogalanin, which is encoded by the GAL gene. The sequence of this gene is highly conserved among mammals, showing over 85% homology
between rat, mouse, porcine, bovine, and human sequences. In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein.
These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin
secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin, and other regulatory peptides, in their autologous species.
The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of preprogalanin. The other two peptides, galanin-like peptide
(GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the preproGALP gene. GALP and alarin are produced by different post-translational splicing
of this gene.
(GPCR) superfamily. Galanin receptors are expressed in the central nervous system
, in the pancreas
, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons. Experiments into the function of the receptor subtypes involve mostly genetic knockout
mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.
features of the brain in the later stages of Alzheimer’s disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergic
neurons. Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in post-mortem brains of Alzheimer’s patients. The cause and role of this increase is poorly understood.
It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive
function in patients by decreasing the amount of acetylcholine
available to these neurons.
A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid
toxicity. It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription
of factors that promote neuron function and survival. It is still unclear as to whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.
is an inhibitor of glutamate but not GABA
and, as such, is capable of increasing the seizure threshold
and, therefore, is expected to act as an anticonvulsant
. To be specific, GalR1 has been linked to the suppression of spontaneous seizures. Agonist antiepileptic drug candidate NAX 5055.
of the dorsal root ganglion
(DRG). Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P
. This suggests that the cell loss by apoptosis
that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.
after crush injury, which is linked to long-term functional problems.
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
encoded by the GAL gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.
The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor. Galanin is linked to a number of diseases including Alzheimer’s disease, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
as well as depression, eating disorders and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Galanin appears to have neuroprotective
Neuroprotection
Neuroprotection within the nervous system protects neurons from apoptosis or degeneration, for example following a brain injury or as a result of chronic neurodegenerative diseases....
activity as its biosynthesis is increased 2-10 fold upon axotomy
Axotomy
An axotomy is the cutting or otherwise severing an axon. Derived from axo- and -tomy . This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better understand nervous system diseases.Axotomy may cause neuronal cell...
in the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
as well as when seizure activity occurs in the brain. It may also promote neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
.
Galanin is predominantly an inhibitory, hyperpolarizing
Hyperpolarization (biology)
Hyperpolarization is a change in a cell's membrane potential that makes it more negative. It is the opposite of a depolarization.Hyperpolarization is often caused by efflux of K+ through K+ channels, or influx of Cl– through Cl– channels. On the other hand, influx of cations, e.g...
neuropeptide and as such inhibits neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
, and norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, and also with other neuromodulators such as Neuropeptide Y
Neuropeptide Y
Neuropeptide Y is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system."NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy." The main effect is increased food...
, Substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, and Vasoactive intestinal peptide
Vasoactive intestinal peptide
Vasoactive intestinal peptide also known as the vasoactive intestinal polypeptide or VIP is a peptide hormone containing 29 amino acid residues that is produced in many tissues of vertebrates including the gut, pancreas and suprachiasmatic nuclei of the hypothalamus in the brain...
.
Discovery
Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine. The structure of galanin was determined in 1983 by the same team, and its cDNA of galanin was cloned from rat anterior pituitary library in 1987.Tissue distribution
Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the hypothalamusHypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, with lower levels in the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
and brainstem. Gastrointestinal galanin is most abundant in the duodenum
Duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
, with lower concentrations in the stomach, small intestine, and colon.
Structure
| Species | 1 | 6 | 11 | 16 | 21 | 26 |
|---|---|---|---|---|---|---|
| Pig | G W T L N | S A G Y L | L G P H A | I D N H R | S F H D K | Y G L A * |
| Man | G W T L N | S A G Y L | L G P H A | V G N H R | S F S D K | N G L T S ** |
| Cow | G W T L N | S A G Y L | L G P H A | L D S H R | S F Q D K | H G L A * |
| Rat | G W T L N | S A G Y L | L G P H A | I D N H R | S F S D K | H G L T* |
| * C-terminal amide ** C-terminal free acid | ||||||
Galanin is a peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as preprogalanin, which is encoded by the GAL gene. The sequence of this gene is highly conserved among mammals, showing over 85% homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
between rat, mouse, porcine, bovine, and human sequences. In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein.
These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin, and other regulatory peptides, in their autologous species.
The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of preprogalanin. The other two peptides, galanin-like peptide
Galanin-like peptide
Galanin-like peptide is a neuropeptide present in humans and other mammals. It is a 60-amino acid polypeptide produced in the arcuate nucleus of the hypothalamus and the posterior pituitary gland. It is involved in the regulation of appetite and may also have other roles such as in inflammation,...
(GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the preproGALP gene. GALP and alarin are produced by different post-translational splicing
RNA splicing
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
of this gene.
Receptors
Galanin signalling occurs through three classes of receptors, GALR1, GALR2, and GALR3, which are all part of the G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) superfamily. Galanin receptors are expressed in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons. Experiments into the function of the receptor subtypes involve mostly genetic knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.
Alzheimer’s Disease
One of the pathologicalPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
features of the brain in the later stages of Alzheimer’s disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergic
Cholinergic
The word choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation. Found in most animal tissues, choline is a primary component of the neurotransmitter acetylcholine and functions with inositol as a basic constituent of lecithin...
neurons. Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in post-mortem brains of Alzheimer’s patients. The cause and role of this increase is poorly understood.
It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
function in patients by decreasing the amount of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
available to these neurons.
A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
toxicity. It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of factors that promote neuron function and survival. It is still unclear as to whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.
Epilepsy
Galanin in the hippocampusHippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
is an inhibitor of glutamate but not GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
and, as such, is capable of increasing the seizure threshold
Seizure threshold
A seizure threshold is the balance between excitatory and inhibitory forces in the brain which affects how susceptible one is to seizures. Those diagnosed with epilepsy or certain other neurological conditions are vulnerable to sudden new seizures if the threshold is upset, and so must be...
and, therefore, is expected to act as an anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
. To be specific, GalR1 has been linked to the suppression of spontaneous seizures. Agonist antiepileptic drug candidate NAX 5055.
In development
It has been shown that galanin plays a role in the control of the early post-natal neural developmentNeural development
Neural development comprises the processes that generate, shape, and reshape the nervous system, from the earliest stages of embryogenesis to the final years of life. The study of neural development aims to describe the cellular basis of brain development and to address the underlying mechanisms...
of the dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
(DRG). Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
. This suggests that the cell loss by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.
After injury
In vitro experiments show that DRG cells removed from galanin mutants have impaired abilities to extend neurites in culture, in that the number of cells producing neurites is decreased by a third and the mean length of these processes was halved when compared to wild-type controls. In vivo, many of the actions of galanin in the brain after an injury are similar to those observed in the developing DRG. Adult mutant animals have been shown to be 35% less capable of regenerating the sciatic nerveSciatic nerve
The sciatic nerve is a large nerve fiber in humans and other animals. It begins in the lower back and runs through the buttock and down the lower limb...
after crush injury, which is linked to long-term functional problems.