Guanylate cyclase is also known as guanyl cyclase, guanylyl cyclase, or GC.
It is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) and pyrophosphate:
GTP = 3′,5′-cyclic GMP + diphosphate.
It is often part of the G protein signaling cascade that is activated by low intracellular calcium levels and inhibited by high intracellular calcium levels.
It plays a critical role in cellular signaling as cGMP acts as a second messenger in various physiological processes, such as vasodilation, smooth muscle relaxation, and sensory signal transduction.
There are two main types of guanylate cyclase: Soluble Guanylate Cyclase (sGC):
Found in the cytoplasm.
Functions as a receptor for nitric oxide (NO), which activates it to produce cGMP.
Key in cardiovascular regulation, including blood pressure and vascular tone.
Membrane Guanylate Cyclase:
A transmembrane protein with extracellular ligand-binding and intracellular catalytic domains.
Activated by specific ligands like natriuretic peptides or bacterial toxins.
Involved in processes such as intestinal fluid regulation and sensory signaling.
cGMP generated by GC is degraded by phosphodiesterases, ensuring tight regulation of its signaling pathways.
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.
Soluble guanylate cyclase catalyzes the formation of cyclic GMP upon interaction with nitric oxide to activate a number of downstream signaling cascades, which can compensate for defects in this pathway and resulting losses in regulatory myocardial and vascular cellular processes due to cardiovascular complications.
Like cAMP, cGMP is an important second messenger that internalizes the message carried by intercellular messengers such as peptide hormones and nitric oxide and can also function as an autocrine signal.
In smooth muscle, cGMP is the signal for relaxation, and is coupled to many homeostatic mechanisms including regulation of vasodilation, vocal tone, insulin secretion, and peristalsis.
Once formed, cGMP can be degraded by phosphodiesterases, which themselves are under different forms of regulation, depending on the tissue.
Guanylate cyclase is found in the retina (RETGC) and modulates visual phototransduction in rods and cones.
Guanylate cyclase Is part of the calcium negative feedback system that is activated in response to the hyperpolarization of the photoreceptors by light.
Guanylate cyclase causes less intracellular calcium, which stimulates guanylate cyclase-activating proteins.
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.
Guanylate cyclase 2C (GC-C) is an enzyme expressed mainly in intestinal neurons, and its activation of GC-C amplifies the excitatory cell response that is modulated by glutamate and acetylcholine receptors.
GC-C, is mainly for its secretory regulation in the intestinal epithelium, is also expressed in the brain: the somata and dendrites of dopaminergic neurons in the ventral tegmental area (VTA) and the substantia nigra, and may play a role in attention deficiency and hyperactive behavior.
Soluble guanylate cyclase contains a molecule of heme, and is activated primarily by the binding of nitric oxide (NO) to it.
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.
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 disease.
Increased intracellular cGMP has been shown to contribute to excessive neuron excitability and locomotor activity.
There are membrane-bound (type 1, guanylate cyclase-coupled receptor) and soluble (type 2, soluble guanylate cyclase) forms of guanylate cyclases.
Cone dystrophy (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 in the guanylate cyclase activator.