8.A.85 The Guanylate Cyclase (GC) Family cGMP controls many cellular functions ranging from growth, viability, and differentiation to contractility, secretion, and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains (Kuhn 2016). These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular COOH-terminal catalytic (cGMP synthesizing) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides, regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptides, stimulating endochondral ossification. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina, and their activation by intracellular Ca²⁺-regulated proteins is essential for vision. Finally, in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO₂ and by peptidergic guanylins and nonpeptidergic odorants as well as by low temperatures, which have implications for social behaviors (Kuhn 2016).
This family belongs to the Adenylate/Guanylate Cyclase (A/GCyc) Superfamily.
References:
Dickey, D.M., A.B. Edmund, N.M. Otto, T.S. Chaffee, J.W. Robinson, and L.R. Potter. (2016). Catalytically Active Guanylyl Cyclase B Requires Endoplasmic Reticulum-mediated Glycosylation, and Mutations That Inhibit This Process Cause Dwarfism. J. Biol. Chem. 291: 11385-11393.
Frees, A., K.B. Assersen, M. Jensen, P.B.L. Hansen, P.M. Vanhoutte, K. Madsen, A. Federlein, L. Lund, A. Toft, and B.L. Jensen. (2020). Natriuretic peptides relax human intrarenal arteries through natriuretic peptide receptor type-A recapitulated by soluble guanylyl cyclase agonists. Acta Physiol (Oxf) e13565. [Epub: Ahead of Print]
Koller, K.J., D.G. Lowe, G.L. Bennett, N. Minamino, K. Kangawa, H. Matsuo, and D.V. Goeddel. (1991). Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 252: 120-123.
Kuhn, M. (2016). Molecular Physiology of Membrane Guanylyl Cyclase Receptors. Physiol. Rev. 96: 751-804.
Legueux-Cajgfinger, Y., M. Velusamy, S. Fathallah, B. Vallin, L. Duca, M. Dauchez, P. Vincent, I. Limon, and R. Blaise. (2023). Unraveling the inhibitory mechanism of adenylyl cyclase 8E: New insights into regulatory pathways of cAMP signal integration. Biochim. Biophys. Acta. Mol. Cell Res 1871: 119645. [Epub: Ahead of Print]
Smith, M., N. Whittock, A. Searle, M. Croft, C. Brewer, and M. Cole. (2007). Phenotype of autosomal dominant cone-rod dystrophy due to the R838C mutation of the GUCY2D gene encoding retinal guanylate cyclase-1. Eye (Lond) 21: 1220-1225.
Steinbrecher, K.A. (2014). The multiple roles of guanylate cyclase C, a heat stable enterotoxin receptor. Curr Opin Gastroenterol 30: 1-6.
Examples:
TC#	Name	Organismal Type	Example
8.A.85.1.1	Heat-stable enterotoxin receptor, STAR, of 1073 aas and 2 or 3 TMSs, also called GUCY2C or GUC2C. It is the receptor for the E. coli heat-stable enterotoxin, STa. STAR is expressed primarily on intestinal epithelial cells and STa markedly stimulates the accumulation of cGMP in cells expressing guanyl cyclase-C which is also activated by the endogenous peptides guanylin and uroguanylin. Activation initiates salt and water movement in the intestine. STa, deregulates this pathway and causes secretory diarrhea. (Steinbrecher 2014).		STAR of Homo sapiens

8.A.85.1.2	Atrial natriurentic peptide receptor of 1047 aas, NPR2, ANPRB, of 1047 aas and probably 2 - 3 TMSs. Receptor for the C-type natriuretic peptide NPPC/CNP hormone. It has guanylate cyclase activity upon binding of its ligand. May play a role in the regulation of skeletal growth. Mutations cause dwarfism (Dickey et al. 2016).		NPR2 of Homo sapiens

8.A.85.1.3	*Retinal guanylate cyclase 1, GUCY2D, CORD6, GUC1A4, GUC2D, RETGC, RETGC1, OF 1103 aas. Mutations cause autosomal dominant cone-rod dystrophy (Smith et al.* 2007).**		GC2D of Homo sapiens

8.A.85.1.4	Putative adenylate cyclase, CyaA, of 609 aas and 3 putative TMSs.		CyaA of Bdellovibrio bacteriovorus

8.A.85.1.5	Putative adenylyl cyclase class-3/4/guanylyl cyclase of 500 aas and 4 TMSs near the N-terminus of the protein.		Adenylyl cyclase of Marinobacter hydrocarbonoclasticus

8.A.85.1.6	Natriuretic peptide receptor 1, NPR1 or ANPRA, of 1061 aas and one N-terminal TMS. It is the receptor for the atrial natriuretic peptide NPPA/ANP and the brain natriuretic peptide NPPB/BNP which are potent vasoactive hormones playing a key role in cardiovascular homeostasis. It has guanylate cyclase activity upon binding of the ligand (Koller et al. 1991). Natriuretic peptides relax human intrarenal arteries through natriuretic peptide receptor type-A recapitulated by soluble guanylyl cyclase agonists (Frees et al. 2020).		NPR1 of Homo sapiens

8.A.85.1.7	Uncharacterized protein of 787 aas and 1 (N-terminus) + 1 (at residue 350) + 1 - 3 TMSs (at residues 400 - 470) followed by a hydrophilic domain that is homologous to other members of this family. The first 470 aas are not homologous to other members if this family.		UP of Pelagibacteraceae bacterium TMED13 (marine metagenome)

8.A.85.1.8	Putative K⁺ channel, ACα, of 669 aas with two very hydrophobic putative TMSs following by 3 weakly hydrophone potential TMSs.		ACα of Plasmodium falciparum

8.A.85.1.9	Adenylyl cyclase 8 of 1251 aas and 12 TMSs in a 6 + 6 TMS pattern. It catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affects processes suche as synaptic plasticity and insulin secretion. It plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation. It also plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and the glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation, leading to vesicle pool replenishment. A dual inhibitory mechanism provides a level of regulation of cAMP-dependent signals integration (Legueux-Cajgfinger et al. 2023).		AC8 of Homo sapiens

Examples:
TC#	Name	Organismal Type	Example
8.A.85.2.1	Putative adenylate cyclase, CyaC of 483 aas and 6 - 8 TMSs with a 6 TMS N-terminal domain.		CyaC of Bdellovibrio exovorus

Examples:
TC#	Name	Organismal Type	Example
8.A.85.3.1	Adenylate cyclase with N-terminal 6 TMS domain of 571 aas.		Cya of Desulfobacterium autotrophicum

8.A.85.3.2	Metal-dependent phosphohydrolase of 428 aas and 6 N-terminal TMSs.		Phosphohydrolase of Shewanella loihica

8.A.85.3.3	Uncharacterized HD domain-containing protein of 799 aas and 7 N-terminal TMSs.		*UP of Butyrivibrio* sp. CB08**

Examples:
TC#	Name	Organismal Type	Example
8.A.85.9.5	Uncharacterized membrane protein YgaE (UPF0421/DUF939 family) of 410 aas and 5 or 6 N-terminal TM		UP of Micromonospora echinospora