In endothelial cells, ET-1 is predominant, while ET-2 and ET-3 are virtually undetectable. The mRNAs for all three endothelins are present in human kidney and the intestinal jejunum, while in the nervous system the mRNA for ET-1 is the major species. Radioligand binding studies with the isoforms of ET have indicated the presence of two classes of receptors. Type I receptors are involved with vasoconstriction, bronchoconstriction, and stimulation of aldosterone biosynthesis. Type II receptors are linked to the inhibition of platelet aggregation and vasorelaxation. Through molecular cloning of ET receptors, the deduced amino acid sequence of seven ET receptors has been elucidated. They can be divided into two classes designated ETA and ETB; see Table 1. Both classes of endothelin receptors belong to the seven-transmembrane, G-protein-coupled superfamily.

Table1. Properties of Endothelium Receptors

The current view is that ETA endothelin receptors mediate the paracrine (vasoconstrictor) actions of ET-1, while the ETB receptors mediate the more “nonselective” actions of endothelins, including autocrine actions related to vasodilation (Figure 1D).

Fig1. The endothelin gene, their hormones and receptor families and receptor signal transduction events in the vasculature resulting in a reduction of blood pressure. (A) Processing of the endothelin prepro ET-1 mRNA. The human genome has three separate genes which individually code for three endothelin amino acid sequences; they are ET-1, ET-2, and ET-3. The ET-1 prepro endothelial-1 has 212 amino acids, the “big” ET-1 has 38 amino acids, and the mature ET-1 has 21 amino acids. (B) Isoforms of endothelins. There are three separate biologically active isoforms of endothelin which are all about the same pro-size; they are ET-1 (90 amino acids, [aa], blue color), ET-2 (89 aa, red color), and ET-3 (93 aa, green). Panel B shows the amino acid sequence for ET-1, ET-2, and ET-3. The reference amino acid sequence is ET-1; all the residues are colored blue. ET-2 has eight amino acids residues different from that of ET-1; each are marked by the red color. ET-3 has 16 aa residues (colored green) that are different from ET-1. The vertical arrow indicates the site of proteolytic cleavage by the endothelin-converting enzyme (ECE), which generates the three mature, biologically active endothelins. The two solid lines at the left end loops indicate the presence of their two disulfide linkages for each of the three endothelins. Also shown in the bottom row is the amino acid sequence of the structurally homologous sarafotoxin b, which is present in the venom of the burrowing Egyptian asp, Atractaspesis engaddensis. The sarafotoxin b is a potent vasoconstrictor in cerebral arteries of some mammals where it is employed to protect the asp. (C) Schematic presentation of four families of endothelin receptors. At present there are at least four known endothelin receptors; they are designated as ETA, ETB1, ETB2, and ETC, all of which are G protein-coupled receptors. Ligand binding of the endothelins to their appropriate receptor(s) results in the activation of the receptor and stimulates an increase of the concentration of the intracellular-free calcium. Activation of the ETA receptor leads to vasoconstriction whereas activation of the ETB1 receptor leads to vasodilation. The biological function of the receptor ETC is not yet clear. (D) Biological responses mediated by endothelins in the presence of smooth muscle. In Panel D, the two endothelial producing cells are colored green while the two adjacent endothelial responding smooth muscle cells are colored tan. The endothelial cell on the left has the capability to positively respond to ten hormones (see left rectangle +) and to stimulate gene transcription and production of ET-1 for secretion. This panel is described in more detail in section III.F.3. Abbreviations: Ca2+, cytosolic calcium; NO, nitric oxide; PLC, phospholipase C; PKC, protein kinase C; DAG, diacylglycerol; IP3; inositol triphosphate; ECE, endothelium converting enzyme; PT, pertussis toxin; PLD; phospholipase D; TK, tyrosine kinase.

At present there are at least four known endothelin receptors; they are designated as ETA, ETB1, ETB2 and ETC, all of which are G protein-coupled receptors. Ligand binding of the endothelins to their appropriate receptor(s) results in the activation of the receptor and stimulates an increase of the concentration of the intracellular free calcium. Activation of the ETA receptor leads to vasoconstriction, whereas activation of the ETB1 receptor leads to vasodilation. The biological function of the receptor ETC is not yet clear.

Simultaneous biological responses mediated by endothelins in adjacent cells are illustrated in Figure 1D.

In this model, receptors for ET-1 are present in endothelial cells of the vascular system throughout the body and also the smooth muscle cells that are associated with the endothelial cells. Table 1 summarizes the relative ligand affinity of ET-1 and ET-3 for the three receptor isoforms, ETA, ETB1, and ETB2.

Based on the DNA sequence, it has been determined that the sequence homology is ~88–90% identical between human and rat receptors for both the ETA and ETB receptors. In contrast, surprisingly, the degree of homology between the ETA and ETB receptors within a given species (e.g., the human) is only 55%, suggesting that they have quite different responsibilities. Both of these receptors mechanistically are G-protein-coupled and when they are ligand activated, the signal trans duction for both receptors results in an increase in intracellular free calcium concentration. As shown in Figure 1D for smooth muscle cells, depending upon which signal transduction pathway(s) are used, the end result can be quite different.

Receptors for ET-1 are present in endothelial cells of both the vascular system throughout the body and also the associated smooth muscle cells that are intimately associated with the endothelial cells.

Table1 summarizes the relative ligand affinity of ET-1 and ET-3 for the three receptor isoforms, ETA, ETB1, and ETB2. In Figure 1D, the two endothelial cells are colored green while the two adjacent smooth muscle cells are colored tan. The endothelial cell on the left has the capability to positively respond to five hormones (see large rectangle with the + on the arrow) so as to stimulate gene transcription and to secrete ET-1. In addition the green endothelial cell on the left has the capability to partially respond to five different hormones (see rectangle with − on the arrow) which diminishes the transcription of the ET-1 genes and the secretion of ET-1. The positive endothelial cell’s ET-1 secretion of ET-1 is sent to the smooth muscle cell on the bottom left where it binds to the ET-1 plasma membrane receptor labeled (A). This results in the activation of phospholipase C which then stimulates IP3 which, in turn, increases the intracellular Ca2+concentration and also activates the H+/Na+ channels that collectively cause the smooth muscle cells to engage in constriction.

The endothelial cell membrane’s ET-1 receptor labeled (B), on the upper right endothelial cell, responds to the incoming diminished ET-1 “signal” from the second group of five hormones received by the left endothelial cell. However, there is still a significant increase in the right-hand endothelial cell’s intracellular Ca2+ concentration. This causes the calmodulin, by binding Ca2+, to become active and activate the eNOS enzyme to secrete nitric oxide (NO). The NO, which has a half-life in cells of ~5 seconds, can rapidly diffuse through the cell membrane of the right tan cell and bind to a nearby sGC (soluble guanylyl cyclase) which activates the cyclic GMP pathway. This, in turn, causes the smooth muscle cells to engage in “relaxation.”

Note the three labels underneath the two smooth muscle cells; they are Constriction, Relaxation, and Proliferation. Each label describes the response initiated by the ET-1 signal transduction received. The right hand smooth muscle cell also can respond directly to ET-1 binding to its membrane receptor labeled A, which activates PLC, to produce DAG, which then activates PKC and finally MAPK. This leads to proliferation of this smooth muscle cell. In the left-hand smooth muscle cell, it is described that an increase in intracellular Ca2+ can lead to stimulation of “constriction” of smooth muscle cell membranes. This can contribute to an increase in blood pressure.

The ETA is known to mediate the process of vasoconstriction (raises blood pressure) while ETB receptors mediate the process of vasodilation (lowers blood pressure). As for the subtypes of the ETB receptor, ETB1 mediates vasodilation while ETB2 mediates vasoconstriction.

Based on the DNA sequence, it has been determined that the sequence homology is ~88–90% identical between human and rat receptors for both the ETA and ETB receptors. In contrast, and surprisingly, the degree of homology between the ETA and ETB receptors within a given species (e.g., the human) is only 55%, suggesting that they have quite different responsibilities.

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مواضيع ذات صلة

Kallikreins and Kinins

Biological Actions of NO

Red Blood Cell Enzymopathies- Metabolic Pathways

Hemoglobins with Decreased Oxygen Affinity

Chemistry, Biosynthesis, and Secretion of Nitric Oxide System

Chemistry, Biosynthesis, and Secretion of Endothelins

Chemistry, Biosynthesis, and Secretion of ANP

Hemoglobins with Increased Oxygen Affinity

Specific Enzymes are Associated with Compartments Separated by the Mitochondrial Membranes

ATP Acts as the “Energy Currency” of The Cell

Living Organisms Package Transition Metals Within Organometallic Complexes

Androgen Biosynthesis