Calcitonin receptor-like (CALCRL), also known as the calcitonin receptor-like receptor (CRLR), is a human
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
; it is a
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for
calcitonin gene-related peptide
Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 ( intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produc ...
.
Function
The protein encoded by the CALCRL gene 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 ...
related to the
calcitonin receptor
The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism.
CT works by activating the G ...
. CALCRL is linked to one of three single transmembrane domain
receptor activity-modifying protein
Receptor activity-modifying proteins (RAMPs) are a class of protein that interact with and modulate the activities of several Class B G protein-coupled receptors including the receptors for secretin, calcitonin (CT), glucagon, and vasoactive in ...
s (RAMPs) that are essential for functional activity.
The association of CALCRL with different RAMP proteins produces different receptors:
* with
RAMP1
Receptor activity modifying protein 1 is a protein that in humans is encoded by the ''RAMP1'' gene.
The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity mod ...
: produces a
CGRP
Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 ( intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produc ...
receptor
* with
RAMP2
Receptor activity modifying protein 2, also known as RAMP2, is a protein which in humans is encoded by the ''RAMP2'' gene.
Function
The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, calle ...
: produces an
adrenomedullin
Adrenomedullin (ADM or AM) is a vasodilator peptide hormone of uncertain significance in human health and disease. It was initially isolated in 1993 from a pheochromocytoma, a tumor of the adrenal medulla: hence the name.
In humans ADM is encoded ...
(AM) receptor, designated AM
1
* with
RAMP3
Receptor activity modifying protein 3, also known as RAMP3, is a human gene.
The protein encoded by this gene is a member of the RAMP family of single-transmembrane-domain proteins, called receptor (calcitonin) activity modifying proteins (RAMPs) ...
: produces a dual CGRP/AM receptor designated AM
2
These receptors are linked to the
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their act ...
Gs,
which activates
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
and activation results in the generation of
intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
cyclic adenosine monophosphate
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP).
CGRP receptors are found throughout the body, suggesting that the protein may modulate a variety of physiological functions in all major systems (e.g.,
respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
,
endocrine
The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neu ...
,
gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
,
immune
In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
, and
cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
).
Wounds
In wounds, CGRP receptors found in
nerve cells
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
deactivate the immune system, to prevent collateral damage in case of a clean wound (common case). In very preliminary research, nerve blockers like e.g.
lidocaine
Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...
or
botox
Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neurom ...
have been demonstrated to
block
Block or blocked may refer to:
Arts, entertainment and media Broadcasting
* Block programming, the result of a programming strategy in broadcasting
* W242BX, a radio station licensed to Greenville, South Carolina, United States known as ''96.3 ...
CGRP cascade, thereby allowing immune system involvement and control of pathogens, resulting in complete control and recovery.
Structure
CALCRL associated with RAMP1 produces the CGRP receptor which is a trans-membrane protein receptor that is made up of four chains. Two of the four chains contain unique sequences. It is a heterodimer protein composed of two polypeptide chains differing in composition of their amino acid residues. The sequence reveals multiple hydrophobic and hydrophilic regions throughout the four chains in the protein.
[; ]
The CGRP family of receptors including CALCRL can couple to G-protein
Gαs
The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein.
Gsα is the founding m ...
,
Gαi
Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o (Gi /Go ) family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred ...
and
Gαq
Gq protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gq/11 (Gq/G11) family or Gq/11/14/15 family to include closely related family members. G alpha subunits may be referred ...
subunits to transduce their signals. Furthermore binding of ligands to CALCRL can bias coupling to these G-protein.
Peptide agonist bind to the extracellular loops of CALCRL. This binding in turn causes TM5 (
transmembrane helix
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...
5) and TM6 to pivot around TM3 which in turn facilitates Gαs binding.
Adrenomedullin receptor
Expression
The RNA expression charts show a high level in fetal lung.
Clinical significance
Calcitonin gene-related peptide receptor antagonists are approved for the treatment of
migraine
Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
.
References
Further reading
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External links
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{{Growth factor receptor modulators
G protein-coupled receptors