Calcitonin gene-related peptide
Encyclopedia
Calcitonin gene related peptide (CGRP) is a member of the calcitonin
family of peptide
s, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid
peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11. The less-studied β-CGRP differs in three amino acids (in humans) and is encoded in a separate gene in the same vicinity.
are the main source of CGRP. CGRP is thought to play a role in cardiovascular homeostasis and nociception
.
called calcitonin receptor-like receptor (CALCRL
) and a receptor activity-modifying protein
(RAMP1
). CGRP receptor
s are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., respiratory
, endocrine
, gastrointestinal, immune
, and cardiovascular).
5HT1
receptor agonists such as sumatriptan
increase intracellular calcium, which cause decreases in CGRP promoter activity. Botulinum toxin
type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25
protein. Receptor antagonists such as telcagepant
, which is in phase III from Merck Pharmaceuticals, also have promise in limiting the effects of CGRP.
and Temporomandibular joint disorder
patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.
Preclinical evidence suggests that, during a migraine
, activated primary sensory neurons (meningeal nociceptors) in the trigeminal ganglion
release CGRP from their peripherally projecting nerve endings located within the meninges
. This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell
degranulation, and plasma extravasation. Human observations have further implicated the role of CGRP in the pathophysiology of migraine. Activation of primary sensory neurons in the trigeminal vascular system in humans can cause the release of CGRP. During some migraine attacks, increased concentrations of CGRP can be found in both saliva and plasma drawn from the external jugular vein. Furthermore intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.
The source of CGRP in migraine
(and other pain conditions) is largely thought to derive from the peptidergic peripheral innervation where alpha-CGRP is the predominant isoform produced by sensory neurons. It is the alpha-CGRP isoform that is presumed to be the primary contributor to pain mechanisms. However, more recent evidence demonstrates that CGRP is expressed among keratinocytes of the epidermis where it is predominantly the beta form. Furthermore, CGRP expression in keratinocytes is substantially increased in certain human chronic pain conditions and animal models of induced chronic pain conditions, whereas the alpha-CGRP containing peptidergic innervation is decreased in painful skin sites. Therefore, keratinocyte-derived beta-CGRP may have an important role in chronic pain
mechanisms, as well as other dermatologic disorders known to involve changes in CGRP levels, such as psoriasis. Although very little is known about the functional differences between these two isoforms, research has demonstrated that the beta-CGRP is also expressed among enteric neurons of the gut, and CGRP has been implicated in mechanisms of visceral pain disorders, such as irritable bowel syndrome.
Calcitonin
Calcitonin is a 32-amino acid linear polypeptide hormone that is producedin humans primarily by the parafollicular cells of the thyroid, and in many other animals in the ultimobranchial body. It acts to reduce blood calcium , opposing the effects of parathyroid hormone . Calcitonin has been found...
family of 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...
s, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11. The less-studied β-CGRP differs in three amino acids (in humans) and is encoded in a separate gene in the same vicinity.
Function
CGRP is one of the most abundant peptides produced in both peripheral and central neurons. It is the most potent peptide vasodilator and can function in the transmission of pain. In the spinal cord, the function and expression of CGRP may differ depending on the location of synthesis. CGRP is derived mainly from the cell bodies of motor neurons when synthesized in the anterior horn of the spinal cord and may contribute to the regeneration of nervous tissue after injury. Conversely, CGRP is derived from posterior root ganglion when synthesized in the posterior horn of the spinal cord and may be linked to the transmission of pain. In the trigeminal vascular system, the cell bodies on the trigeminal ganglionTrigeminal ganglion
The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater, covering the trigeminal impression near the apex of the petrous part of the temporal bone.-Relations:It is somewhat crescentic in shape, with its convexity...
are the main source of CGRP. CGRP is thought to play a role in cardiovascular homeostasis and 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...
.
Receptors
CGRP mediates its effects though a heteromeric receptor composed of a 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...
called calcitonin receptor-like receptor (CALCRL
CALCRL
Calcitonin receptor-like , also known as the calcitonin receptor-like receptor , is a human protein.- Function :The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor...
) and a receptor activity-modifying protein
Receptor activity-modifying protein
Receptor activity-modifying proteins are a class of protein which interact with and modulate the activities of several Class B G Protein-Coupled Receptors including the receptors for secretin, calcitonin , glucagon, and vasoactive intestinal peptide...
(RAMP1
RAMP1
Receptor activity modifying protein 1 is a protein that in humans is encode by the RAMP1 gene.The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor activity modifying proteins . RAMPs are type I transmembrane proteins with an...
). CGRP receptor
CALCRL
Calcitonin receptor-like , also known as the calcitonin receptor-like receptor , is a human protein.- Function :The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor...
s are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g., respiratory
Respiratory system
The respiratory system is the anatomical system of an organism that introduces respiratory gases to the interior and performs gas exchange. In humans and other mammals, the anatomical features of the respiratory system include airways, lungs, and the respiratory muscles...
, endocrine
Endocrine system
In physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to the exocrine system, which secretes its chemicals using ducts. It derives from the Greek words "endo"...
, gastrointestinal, immune
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, and cardiovascular).
Regulation
Regulation of the calcitonin gene related peptide (CGRP) gene is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway, cytokines such as TNFα and iNOS.5HT1
5-HT1 receptor
The 5-HT1 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT1 subfamily consists of five G protein-coupled receptors that are coupled to Gi/Go and mediate inhibitory neurotransmission, including 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F...
receptor agonists such as sumatriptan
Sumatriptan
Sumatriptan is a triptan sulfa drug containing a sulfonamide group. It is used for the treatment of migraine headaches. Sumatriptan is produced and marketed by various drug manufacturers with many different trade names such as Sumatriptan, Imitrex, Imigran, Imigran recovery.-Approval and...
increase intracellular calcium, which cause decreases in CGRP promoter activity. Botulinum toxin
Botulinum toxin
Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...
type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25
SNAP-25
Synaptosomal-associated protein 25 is a protein that in humans is encoded by the SNAP25 gene. The SNAP-25 protein is a component of the SNARE complex, which is proposed to account for the specificity of membrane fusion and to directly execute fusion by forming a tight complex that brings the...
protein. Receptor antagonists such as telcagepant
Telcagepant
Telcagepant was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co. In the acute treatment of migraine, it was found to have equal potency to rizatriptan and zolmitriptan in two Phase III clinical trials...
, which is in phase III from Merck Pharmaceuticals, also have promise in limiting the effects of CGRP.
Clinical signficance
Increased levels of CGRP have been reported in migraineMigraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
and Temporomandibular joint disorder
Temporomandibular joint disorder
Temporomandibular joint disorder , or TMJ syndrome, is an umbrella term covering acute or chronic inflammation of the temporomandibular joint, which connects the mandible to the skull. The disorder and resultant dysfunction can result in significant pain and impairment...
patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.
Preclinical evidence suggests that, during a migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
, activated primary sensory neurons (meningeal nociceptors) in the trigeminal ganglion
Trigeminal ganglion
The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater, covering the trigeminal impression near the apex of the petrous part of the temporal bone.-Relations:It is somewhat crescentic in shape, with its convexity...
release CGRP from their peripherally projecting nerve endings located within the meninges
Meninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
. This CGRP then binds to and activates CGRP receptors located around meningeal vessels, causing vasodilation, mast cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
degranulation, and plasma extravasation. Human observations have further implicated the role of CGRP in the pathophysiology of migraine. Activation of primary sensory neurons in the trigeminal vascular system in humans can cause the release of CGRP. During some migraine attacks, increased concentrations of CGRP can be found in both saliva and plasma drawn from the external jugular vein. Furthermore intravenous administration of alpha-CGRP is able to induce headache in individuals susceptible to migraine.
The source of CGRP in migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
(and other pain conditions) is largely thought to derive from the peptidergic peripheral innervation where alpha-CGRP is the predominant isoform produced by sensory neurons. It is the alpha-CGRP isoform that is presumed to be the primary contributor to pain mechanisms. However, more recent evidence demonstrates that CGRP is expressed among keratinocytes of the epidermis where it is predominantly the beta form. Furthermore, CGRP expression in keratinocytes is substantially increased in certain human chronic pain conditions and animal models of induced chronic pain conditions, whereas the alpha-CGRP containing peptidergic innervation is decreased in painful skin sites. Therefore, keratinocyte-derived beta-CGRP may have an important role in chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
mechanisms, as well as other dermatologic disorders known to involve changes in CGRP levels, such as psoriasis. Although very little is known about the functional differences between these two isoforms, research has demonstrated that the beta-CGRP is also expressed among enteric neurons of the gut, and CGRP has been implicated in mechanisms of visceral pain disorders, such as irritable bowel syndrome.