Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a
lyase enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that converts
guanosine triphosphate
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only d ...
(GTP) to
cyclic guanosine monophosphate
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in r ...
(cGMP) and
pyrophosphate
In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...
:
: GTP = 3′,5′-cyclic GMP + diphosphate
It is often part of 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 a ...
signaling cascade that is activated by low
intracellular calcium levels and inhibited by high intracellular calcium levels. In response to calcium levels, guanylate cyclase synthesizes cGMP from GTP. cGMP keeps cGMP-gated
channels open, allowing for the entry of calcium into the cell.
Like
cAMP, cGMP is an important
second messenger that internalizes the message carried by intercellular messengers such as
peptide hormone
Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...
s and
nitric oxide and can also function as an
autocrine signal.
Depending on cell type, it can drive adaptive/developmental changes requiring
protein synthesis. In
smooth muscle, cGMP is the signal for relaxation, and is coupled to many
homeostatic mechanisms including regulation of
vasodilation
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...
, vocal tone,
insulin secretion, and
peristalsis
Peristalsis ( , ) is a radially symmetrical contraction and relaxation of muscles that propagate in a wave down a tube, in an anterograde direction. Peristalsis is progression of coordinated contraction of involuntary circular muscles, whic ...
. Once formed, cGMP can be degraded by
phosphodiesterase
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many ot ...
s, which themselves are under different forms of regulation, depending on the tissue.
Reaction
Guanylate cyclase catalyzes the reaction of
guanosine triphosphate
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only d ...
(GTP) to
3',5'-cyclic guanosine monophosphate (cGMP) and
pyrophosphate
In chemistry, pyrophosphates are phosphorus oxyanions that contain two phosphorus atoms in a P–O–P linkage. A number of pyrophosphate salts exist, such as disodium pyrophosphate (Na2H2P2O7) and tetrasodium pyrophosphate (Na4P2O7), among othe ...
:
Image:Guanosintriphosphat_protoniert.svg, GTP
Image:CGMP.svg, cGMP
Effects
Guanylate cyclase is found in the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
(RETGC) and modulates
visual phototransduction Visual phototransduction is the sensory transduction process of the visual system by which light is detected to yield nerve impulses in the rod cells and cone cells in the retina of the eye in humans and other vertebrates. It relies on the visual ...
in
rods and
cone
A cone is a three-dimensional geometric shape that tapers smoothly from a flat base (frequently, though not necessarily, circular) to a point called the apex or vertex.
A cone is formed by a set of line segments, half-lines, or lines con ...
s. It is part of the
calcium negative feedback system that is activated in response to the hyperpolarization of the
photoreceptors by light. This causes less intracellular calcium, which stimulates
guanylate cyclase-activating proteins (GCAPs). Studies have shown that cGMP synthesis in cones is about 5-10 times higher than it is in rods, which may play an important role in modulating cone adaption to light. In addition, studies have shown that
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
express a higher number of GCAPs than mammals, and that zebrafish GCAPs can bind at least three calcium ions.
Guanylate cyclase 2C
Guanylate cyclase 2C, also known as guanylyl cyclase C (GC-C), intestinal guanylate cyclase, guanylate cyclase-C receptor, or the heat-stable enterotoxin receptor (hSTAR) is an enzyme that in humans is encoded by the ''GUCY2C'' gene.
Guanylyl cyc ...
(GC-C) is an enzyme expressed mainly in intestinal neurons. Activation of GC-C amplifies the excitatory cell response that is modulated by
glutamate and
acetylcholine receptor
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
s. GC-C, while known mainly for its secretory regulation in the
intestinal epithelium
The intestinal epithelium is the single cell layer that form the Lumen (anatomy), luminal surface (lining) of both the Small intestine, small and large intestine (colon) of the Human gastrointestinal tract, gastrointestinal tract. Composed of ...
, is also expressed in the brain. To be specific, it is found in the
somata and
dendrite
Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the ...
s of
dopaminergic neurons in the
ventral tegmental area (VTA) and the
substantia nigra. Some studies implicate this pathway as having a role in
attention deficiency and hyperactive behavior.
Soluble guanylate cyclase contains a molecule of
heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
, and is activated primarily by the binding of nitric oxide (NO) to that heme. sGC is primary receptor for NO a gaseous, membrane-soluble
neurotransmitter. sGC expression has been shown to be highest in the
striatum compared to other brain regions and has been explored as a possible candidate for restoring striatal dysfunction in
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. sGC acts as an intracellular intermediary for regulating dopamine and glutamate. Upregulation, which creates neuronal sensitivity, of the cGMP in a dopamine-depleted striatum has been associated with the symptoms of Parkinson's. Increased intracellular cGMP has been shown to contribute to excessive neuron excitability and locomotor activity. Activation of this pathway can also stimulate
presynaptic glutamate release and cause an upregulation of
AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, better known as AMPA, is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate.
There are several types of glutamatergic ...
receptors postsynaptically.
Types
There are membrane-bound (type 1,
guanylate cyclase-coupled receptor) and soluble (type 2,
soluble guanylate cyclase
Soluble guanylyl cyclase (sGC) is the only known receptor for nitric oxide, NO. It is soluble, i.e. completely intracellular. Most notably, this enzyme is involved in vasodilation. In humans, it is encoded by the genes GUCY1A2, GUCY1A3, GUCY ...
) forms of guanylate cyclases.
Membrane bound guanylate cyclases include an external ligand-binding domain (e.g., for peptide hormones such as
BNP and
ANP), a transmembrane domain, and an internal catalytic domain homologous to
adenylyl 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 ...
s. Recently, a directly light-gated guanylate cyclase has been discovered in an aquatic fungus.
In the mammalian retina, two forms of guanylate cyclase have been identified, each encoded by separate genes;
RETGC-1 and
RETGC-2. RETGC-1 has been found to be expressed in higher levels in cones compared to rod cells. Studies have also shown that mutations in the RETGC-1 gene can lead to cone-rod dystrophy by disrupting the phototransduction processes.
Mutations
Cone dystrophy
A cone dystrophy is an inherited ocular disorder characterized by the loss of cone cells, the photoreceptors responsible for both central and color vision.
Presentation
The most common symptoms of cone dystrophy are vision loss (age of onset r ...
(COD) is a retinal degradation of photoreceptor function wherein cone function is lost at the onset of the dystrophy but rod function is preserved until almost the end. COD has been linked to several genetic mutations including mutations in the
guanylate cyclase activator 1A (GUCA1A) and guanylate cyclase 2D (GUY2D) among other enzymes. To be specific, GUY2D codes for RETGC-1, which is involved in cone adaptation and photoreceptor sensitivity by synthesizing cGMP. Low concentrations of calcium cause the dimerization of RETGC-1 proteins through stimulation from guanylate cyclase-activating proteins (GCAP). This process happens at amino acids 817-857, and mutations in this region increase RETGC-1 affinity for GCAP. This works to alter the calcium sensitivity of the neuron by allowing mutant RETGC-1 to be activated by GCAP at higher calcium levels than the wild-type. Because RETGC-1 produces cGMP, which keeps cyclic nucleotide-gated channels open allowing the influx of calcium, this mutation causes extremely high intracellular calcium levels. Calcium, which plays many roles in the cell and is tightly regulated, disrupts the membrane when it appears in excess. Also, calcium is linked to
apoptosis by causing the release of
cytochrome c. Therefore, mutations in the RETGC-1 can cause COD by increasing intracellular calcium levels and stimulating cone photoreceptor death.
See also
*
Adenylyl 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 ...
*
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in r ...
*
Guanylyl cyclase activator (protein)
References
External links
*
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EC 4.6.1
Hemoproteins