Receptor Enzymes:- Receptor Guanylyl Cyclases Generate the Second Messenger cGMP

Guanylyl cyclases (Fig. 12–10) are another type of receptor enzyme. When activated, a guanylyl cyclase pro duces guanosine 3,5-cyclic monophosphate (cyclic GMP, cGMP) from GTP:

FIGURE 12–10 Two types (isozymes) of guanylyl cyclase that participate in signal transduction. (a) One isozyme exists in two similar membrane-spanning forms that are activated by their extracellular lig ands: atrial natriuretic factor, ANF (receptors in cells of the renal collecting ducts and the smooth muscle of blood vessels), and guanylin (receptors in intestinal epithelial cells). The guanylin receptor is also the target of a type of bacterial endotoxin that triggers severe diarrhea. (b) The other isozyme is a soluble enzyme that is activated by intra cellular nitric oxide (NO); this form is found in many tissues, including smooth muscle of the heart and blood vessels.

Cyclic GMP is a second messenger that carries different messages in different tissues. In the kidney and intestine, it triggers changes in ion transport and water retention; in cardiac muscle (a type of smooth muscle) it signals relaxation; in the brain it may be involved both in development and in adult brain function. Guanylyl cyclase in the kidney is activated by the hormone atrial natriuretic factor (ANF), which is released by cells in the atrium of the heart when the heart is stretched by increased blood volume. Carried in the blood to the kidney, ANF activates guanylyl cyclase in cells of the collecting ducts (Fig. 12–10a). The resulting rise in [cGMP] triggers increased renal excretion of Na and, consequently, of water, driven by the change in osmotic pressure. Water loss reduces the blood volume, countering the stimulus that initially led to ANF secretion. Vascular smooth muscle also has an ANF receptor— guanylyl cyclase; on binding to this receptor, ANF causes relaxation (vasodilation) of the blood vessel, which increases blood flow while decreasing blood pressure. A similar receptor guanylyl cyclase in the plasma membrane of intestinal epithelial cells is activated by an intestinal peptide, guanylin, which regulates Cl- secretion in the intestine. This receptor is also the target of a heat-stable peptide endotoxin produced by Escherichia coli and other gram-negative bacteria. The elevation in [cGMP] caused by the endotoxin increases Cl secretion and consequently decreases reabsorption of water by the intestinal epithelium, producing diarrhea. A distinctly different type of guanylyl cyclase is a cytosolic protein with a tightly associated heme group (Fig. 12–10b), an enzyme activated by nitric oxide (NO). Nitric oxide is produced from arginine by Ca²⁺ dependent NO synthase, present in many mammalian tissues, and diffuses from its cell of origin into nearby cells. NO is sufficiently nonpolar to cross plasma mem branes without a carrier. In the target cell, it binds to the heme group of guanylyl cyclase and activates cGMP production. In the heart, cGMP reduces the forcefulness of contractions by stimulating the ion pump(s) that ex pel Ca²⁺ from the cytosol.

This NO-induced relaxation of cardiac muscle is the same response brought about by nitroglycerin tablets and other nitrovasodilators taken to relieve angina, the pain caused by contraction of a heart deprived of O2 because of blocked coronary arteries. Nitric oxide is unstable and its action is brief; within seconds of its formation, it undergoes oxidation to nitrite or nitrate. Nitrovasodilators produce long-lasting relax ation of cardiac muscle because they break down over several hours, yielding a steady stream of NO. The value of nitroglycerin as a treatment for angina was discovered serendipitously in factories producing nitroglycerin as an explosive in the 1860s. Workers with angina reported that their condition was much improved during the work week but returned on weekends. The physicians treating these workers heard this story so often that they made the connection, and a drug was born. The effects of increased cGMP synthesis diminish after the stimulus ceases, because a specific phospho diesterase (cGMP PDE) converts cGMP to the inactive 5-GMP. Humans have several isoforms of cGMP PDE, with different tissue distributions. The isoform in the blood vessels of the penis is inhibited by the drug sildenafil (Viagra), which therefore causes cGMP levels to remain elevated once raised by an appropriate stim ulus, accounting for the usefulness of this drug in the treatment of erectile dysfunction.

Most of the actions of cGMP in animals are believed to be mediated by cGMP-dependent protein kinase, also called protein kinase G or PKG, which, when activated by cGMP, phosphorylates Ser and Thr residues in target proteins. The catalytic and regulatory domains of this enzyme are in a single polypeptide (Mr ∼80,000). Part of the regulatory domain fits snugly in the substrate binding site. Binding of cGMP forces this part of the regulatory domain out of the binding site, activating the catalytic domain.

Cyclic GMP has a second mode of action in the vertebrate eye: it causes ion-specific channels to open in the retinal rod and cone cells. We return to this role of cGMP in the discussion of vision in Section 12.7.

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مواضيع ذات صلة

Solute Transport across Membranes:-The β-Adrenergic Receptor Is Desensitized by Phosphorylation

G Protein–Coupled Receptors and Second Messengers:-The -Adrenergic Receptor System Acts through the Second Messenger cAMP

Receptor Enzymes: -The Insulin Receptor Is a Tyrosine-Specific Protein Kinase

Gated Ion Channels:- Neurons Have Receptor Channels That Respond to Different Neurotransmitters

Gated Ion Channels:- Voltage-Gated Ion Channels Produce Neuronal Action Potentials

Gated Ion Channels:- Ion Channels Underlie Electrical Signaling in Excitable Cells

Solute Transport across Membranes:- Defective Ion Channels Can Have Adverse Physiological Consequences

Solute Transport across Membranes:- The Acetylcholine Receptor Is a Ligand-Gated Ion Channel

Solute Transport across Membranes:- The Neuronal Na+ Channel Is a Voltage-Gated Ion Channel

Solute Transport across Membranes: -The Structure of a K+ Channel Reveals the Basis for Its Specificity

Solute Transport across Membranes:- Ion-Channel Function Is Measured Electrically

Solute Transport across Membranes:- Ion-Selective Channels Allow Rapid Movement of Ions across Membranes