Calcitonin gene-related peptide (CGRP) is a naturally occurring substance in the human body, a small protein or neuropeptide composed of 37 amino acids. It exists in two main forms, alpha (α-CGRP) and beta (β-CGRP), which are very similar in structure. CGRP is found throughout the body, playing a role in various physiological processes.
This peptide belongs to the calcitonin family, which also includes other related peptides like adrenomedullin and amylin.
Understanding Calcitonin Gene-Related Peptide
CGRP was initially discovered in 1982 through research into alternative RNA processing of the calcitonin gene. This discovery revealed that while calcitonin is primarily produced in the thyroid, CGRP is predominantly formed in the nervous system.
High concentrations of CGRP are found in sensory ganglia, the trigeminal nerve, and around blood vessels, particularly arteries. It is stored in nerve terminals and released through a calcium-dependent process when nerves are stimulated. This localization highlights its role as a neurotransmitter, mediating communication within the nervous system.
CGRP’s Functions in the Body
CGRP performs diverse physiological roles throughout the body. One of its most recognized functions is vasodilation, meaning it widens blood vessels. Even at very low concentrations, CGRP can cause significant relaxation of blood vessels, increasing blood flow.
CGRP also plays a role in pain signaling. It is released from sensory nerves and is implicated in the transmission of nociceptive (pain) signals. It can contribute to the development of peripheral sensitization, which leads to heightened pain perception.
In addition, CGRP is involved in inflammatory processes. It contributes to neurogenic inflammation, a type of inflammation initiated by nerve activity. This involvement suggests that CGRP helps mediate the body’s response to injury or irritation.
CGRP and Migraine
CGRP has a strong connection to migraine headaches. During a migraine attack, CGRP levels are observed to increase in the external jugular vein, returning to normal as the migraine pain subsides. Infusion of CGRP can trigger migraine-like attacks in individuals prone to migraines.
The trigeminal nervous system, a network of nerves in the head and face, is a primary source of CGRP in migraine. When the trigeminal nerve is activated during a migraine, CGRP is released from its nerve endings, particularly around blood vessels in the meninges, the membranes surrounding the brain. This release contributes to the dilation of blood vessels and neurogenic inflammation in these areas.
The release of CGRP and subsequent neurogenic inflammation further activate trigeminal nerve fibers, intensifying headache pain. This process also contributes to other migraine symptoms like heightened sensitivity to light (photophobia) and sound (phonophobia). The sustained release and increased synthesis of CGRP during an attack are thought to perpetuate migraine symptoms for hours to days.
Therapeutic Approaches Targeting CGRP
Therapeutic strategies target CGRP or its receptor due to its role in migraine. These treatments interrupt the CGRP signaling pathway to prevent or alleviate migraine symptoms. There are two main classes of CGRP-targeted therapies: CGRP receptor antagonists and monoclonal antibodies.
CGRP receptor antagonists, gepants, are small molecules that block the CGRP receptor. By binding to this receptor, gepants prevent CGRP from activating its signaling pathways, inhibiting effects like vasodilation and pain transmission. These oral medications are used for both acute treatment and prevention of migraine.
Monoclonal antibodies (mAbs) are another CGRP-targeted treatment. These proteins bind directly to the CGRP molecule or block its receptor. This prevents CGRP from interacting with its receptor, stopping its activity. These antibodies are administered by injection and are primarily used for migraine prevention, offering a long-term blockade of CGRP activity.