| Guanylate cyclase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 | |||||||||
| Identifiers | |||||||||
| EC no. | 4.6.1.2 | ||||||||
| CAS no. | 9054-75-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
Guanylate cyclase (EC 4.6.1.2, also known asguanyl cyclase,guanylyl cyclase, orGC; systematic nameGTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is alyaseenzyme that convertsguanosine triphosphate (GTP) tocyclic guanosine monophosphate (cGMP) andpyrophosphate:[1]
It is often part of theG proteinsignaling cascade that is activated by lowintracellular calcium levels and inhibited by high intracellular calcium levels. In response to calcium levels, guanylate cyclase synthesizes cGMP from GTP. cGMP keeps cGMP-gatedchannels open, allowing for the entry of calcium into the cell.[2]
LikecAMP, cGMP is an importantsecond messenger that internalizes the message carried by intercellular messengers such aspeptide hormones andnitric oxide and can also function as anautocrine signal.[1] Depending on cell type, it can drive adaptive/developmental changes requiringprotein synthesis. Insmooth muscle, cGMP is the signal for relaxation, and is coupled to manyhomeostatic mechanisms including regulation ofvasodilation, vocal tone,insulin secretion, andperistalsis. Once formed, cGMP can be degraded byphosphodiesterases, which themselves are under different forms of regulation, depending on the tissue.
Guanylate cyclase catalyzes the reaction ofguanosine triphosphate (GTP) to3',5'-cyclic guanosine monophosphate (cGMP) andpyrophosphate:
Guanylate cyclase is found in theretina (RETGC) and modulatesvisual phototransduction inrods andcones. It is part of thecalcium negative feedback system that is activated in response to the hyperpolarization of thephotoreceptors by light. This causes less intracellular calcium, which stimulatesguanylate 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.[3] In addition, studies have shown thatzebrafish express a higher number of GCAPs than mammals, and that zebrafish GCAPs can bind at least three calcium ions.[4]
Guanylate cyclase 2C (GC-C) is an enzyme expressed mainly in intestinal neurons. Activation of GC-C amplifies the excitatory cell response that is modulated byglutamate andacetylcholine receptors. GC-C, while known mainly for its secretory regulation in theintestinal epithelium, is also expressed in the brain. To be specific, it is found in thesomata anddendrites ofdopaminergic neurons in theventral tegmental area (VTA) and thesubstantia nigra. Some studies implicate this pathway as having a role inattention deficiency and hyperactive behavior.[5]
Soluble guanylate cyclase contains a molecule ofheme, and is activated primarily by the binding of nitric oxide (NO) to that heme.[6] sGC is primary receptor for NO a gaseous, membrane-solubleneurotransmitter. sGC expression has been shown to be highest in thestriatum compared to other brain regions and has been explored as a possible candidate for restoring striatal dysfunction inParkinson's disease. 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 stimulatepresynaptic glutamate release and cause an upregulation ofAMPA receptors postsynaptically.[7]
There are membrane-bound (type 1,guanylate cyclase-coupled receptor) and soluble (type 2,soluble guanylate cyclase) forms of guanylate cyclases.
Membrane bound guanylate cyclases include an external ligand-binding domain (e.g., for peptide hormones such asBNP andANP), a transmembrane domain, and an internal catalytic domain homologous toadenylyl cyclases.[8] Recently, a directly light-gated guanylate cyclase has been discovered in an aquatic fungus.[9][10]
In the mammalian retina, two forms of guanylate cyclase have been identified, each encoded by separate genes;RETGC-1 andRETGC-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.
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 including mutations in theguanylate 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 toapoptosis by causing the release ofcytochrome c. Therefore, mutations in the RETGC-1 can cause COD by increasing intracellular calcium levels and stimulating cone photoreceptor death.[11]
Soluble guanylyl cyclase is recognized as the most sensitive physiologic receptor for nitric oxide. Binding of nitric oxide to the heme moiety of the cyclase induces its capacity to synthesize the second messenger cGMP.
{{cite journal}}:Cite journal requires|journal= (help)
