Current understanding of guanylin peptides actions

Abstract

Guanylin peptides (GPs) family includes guanylin (GN), uroguanylin (UGN), lymphoguanylin, and recently discovered renoguanylin. This growing family is proposed to be intestinal natriuretic peptides. After ingestion of a salty meal, GN and UGN are secreted into the intestinal lumen, where they inhibit sodium absorption and induce anion and water secretion. At the same conditions, those hormones stimulate renal electrolyte excretion by inducing natriuresis, kaliuresis, and diuresis and therefore prevent hypernatremia and hypervolemia after salty meals. In the intestine, a well-known receptor for GPs is guanylate cyclase C (GC-C) whose activation increases intracellular concentration of cGMP. However, in the kidney of GC-C-deficient mice, effects of GPs are unaltered, which could be by new cGMP-independent signaling pathway (G-protein-coupled receptor). This is not unusual as atrial natriuretic peptide also activates two different types of receptors: guanylate cylcase A and clearance receptor which is also G-protein coupled receptor. Physiological role of GPs in other organs (liver, pancreas, lung, sweat glands, and male reproductive system) needs to be discovered. However, it is known that they are involved in pathological conditions like cystic fibrosis, asthma, intestinal tumors, kidney and heart failure, obesity, and metabolic syndrome.

Figure 1

Structure and synthesis of human guanylin peptides. Guanylin and uroguanylin have 3 exons and 2 introns. Human preproguanylin has 115, proguanylin 94, and guanylin 15 amino acids. Human preprouroguanylin has 112, prouroguanylin 86, and uroguanylin 16 amino acids. Structures of human guanylin and uroguanylin are compared to the structure of heat-stable enterotoxin of E. coli (STa) at the bottom of the figure. Open circles show identical amino acids in both peptides. Solid circles represent amino acids responsible for peptide sensitivity to chymotrypsin.

Figure 2

Distribution of mRNA for guanylin (black columns) and uroguanylin (white columns) in digestive system. Guanylin is present in all parts of gastrointestinal tract with highest expression in the distal parts of the tract. In contrast, uroguanylin is mostly present in proximal parts where it could play a role in regulating pH after emptying stomach content. PJ: proximal jejunum, DJ: distal jejunum, I: ileum, C: cecum, PC: proximal colon, DC: distal colon (modified from Whitaker et al. [18]).

Figure 3

Guanylin (GN) and uroguanylin (UGN) increasing the intracellular concentration of cGMP are pH dependent. GN is more potent at pH 8.0, and UGN is more potent at pH 5.0 (modified from Hamra et al. [19]).

Figure 4

GC-C-dependent signaling pathway of guanylin peptides in the intestine. Guanylin (GN), uroguanylin (UGN), and heat-stable enterotoxin of E. coli (STa) activate GC-C which increases intracellular concentration of cGMP which in the enterocytes causes the following: inhibits the Na⁺/H⁺ exchanger type 2 (NHE2) and activates protein kinase G type II (PKG II), activates protein kinase A (PKA) directly or indirectly by inhibition of phosphodiesterase III (PDE III) followed by increase in intracellular cAMP concentration. PKA and PKG II activate Cl⁻ and HCO₃ ⁻ secretion via activation of cystic fibrosis transmembrane regulator (CFTR) followed by an activation of the member of Slc26 family which exchanges bicarbonate for chloride.

Figure 5

Guanylate cyclase C: extracellular domain is responsible for ligand binding. Juxtamembrane domain is located near the cell membrane and it is responsible for binding the G-proteins. Kinase homology domain needs to be phosphorylated for pronounced guanylate cyclase activity. Catalytic domain converts GTP to cGMP after ligand binding to extracellular domain. C-terminal tail of the GC-C is unique and it is involved in binding the GC-C to cytoskeleton.

Figure 6

Relative mRNA expression of (a) guanylin (GN) and (b) uroguanylin (UGN) in different mouse nephron segments. GL: glomerulus, PT: proximal tubule, TAL: thick ascending limb of Henle's loop, CD: collecting duct, and GAPDH: glyceraldehyde-3-phosphate dehydrogenase. Mean values: SEM, n = 4. Modified from Potthast et al. [20].

Figure 7

pH dependence of effects of guanylin peptides on membrane voltages (V _m) of human proximal tubule cells. Guanylin (GN) depolarized cells at pH 5.5 as well as pH 8.0. Uroguanylin (UGN) at pH 5.5, activated GC-C and depolarized cells while at pH 8.0 decreased affinity of GC-C for UGN and GC-C independent, G-protein-coupled receptor is activated which leads to hyperpolarization of the cells. Mean values: SEM. Modified from Sindiće et al. [21].

Figure 8

Signaling pathways of guanylin (GN) and uroguanylin (UGN) in the principal cell of the cortical collecting ducts. GN present from glomerular filtration or from paracrine secretion via proximal parts of the nephron segments is degradated by peptidase and therefore not present in the urine. Guanylin peptides (GN and UGN) activate phospholipase A₂ (PLA₂), which leads to an increase in the intracellular concentration of arachidonic acid and an inhibition of luminal ROMK K⁺ channels. ENaC: epithelial sodium channels.