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Receptor Guanylyl Cyclases

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Receptor Guanylyl Cyclases Receptor guanylyl cyclases. S K Wong, D L Garbers J Clin Invest. 1992;90(2):299-305. https://doi.org/10.1172/JCI115862. Research Article Three different guanylyl cyclase cell receptors are known, but others will likely be discovered within the next few years. The general function of these receptors appear to relate to the regulation of fluid volume or fluid movement. New receptors, or possibly the currently known receptors, therefore, may be discovered in areas of the body where fluid volume regulation is important. Such fluids whose volume or composition might be regulated by guanylyl cyclase receptors include synovial fluid, uterine/oviductal luminal fluid, follicular fluid, aqueous humor, cerebral spinal fluid, seminiferous tubule luminal fluid, epididymal luminal fluid, seminal plasma, and airway luminal fluid. The function of the heterodimeric forms of guanylyl cyclase appear to relate to a primary regulation of nitric oxide (or similar molecules) concentrations, which are in turn regulated by a Ca2+/calmodulin-sensitive nitric oxide synthase. Find the latest version: https://jci.me/115862/pdf Perspectives Receptor Guanylyl Cyclases Stephen K.-F. Wong and David L. Garbers Department ofPharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235 Introduction it therefore remains possible that these forms will closely resem- Cyclic GMP is an intracellular signaling molecule that regu- ble known plasma membrane receptor forms. lates ion channels, cyclic AMP concentrations by virtue of its The second major group of guanylyl cyclases appears to effects on selective phosphodiesterases, and protein kinases to exist as heterodimers containing heme as a prosthetic group alter cellular processes and behavior. It is known to act as a (Fig. 1 ), and are activated by vasodilatory agents such as nitro- signaling molecule in many different cells and it likely serves as prusside and nitroglycerin (4). One endogenous physiological a second messenger in virtually all cells. The synthesis of cyclic activator, known as endothelium-derived relaxation factor GMP from GTP is catalyzed by a family of cell surface and (EDRF) is thought to diffuse from endothelial cells to vascular cytoplasmic receptors known as guanylyl cyclases (GC),' each smooth muscle cells where it binds to a heterodimeric form of of which is markedly activated by the binding of specific li- guanylyl cyclase, resulting in its activation, elevations of cyclic gands. A number of different guanylyl cyclase receptors have GMP, and relaxation of smooth muscle (5, 6). Although been isolated and characterized, but it is likely that other EDRF may exist as multiple entities, one active component members of this family remain to be identified, which will even appears to be nitric oxide (7), a short-lived molecule generated further expand the general physiological significance of these by nitric oxide synthase in response to an increase in intracellu- enzyme / receptors. This review discusses the general molecular lar Ca2" (8). structure ofthe known guanylyl cyclases, their ligands and regu- At least one ofthe heterodimeric forms (a,#,) appears to be latory molecules, and their potential or known physiological found in the cytoplasm of various tissues. This enzyme is com- significance. Other recent reviews on the guanylyl cyclase fam- posed of 82-kD (a1 ) and 70-kD (#I ) subunits that appear to be ily include ( 1-3). linked by interchain disulfide bonds (9). Molecular cloning of the cDNA encoding the lung a, and fB subunits (see [3] for Forms ofguanylyl cyclase review) has revealed that the carboxyl-terminal regions are ho- In the mammal, there are now six different forms of guanylyl mologous to each other, and also to the catalytic domain ofthe cyclase known: three are found associated with plasma mem- membrane form of guanylyl cyclase (Fig. 1). A p32-subunit branes, one is soluble, and the fifth and sixth are apparent ( 10), an apparent partner ofan unknown a-subunit, contains a members of the heterodimeric part ofthe family whose cellular potential site for geranylgeranylation; its cellular localization distribution remains to be determined. The guanylyl cyclases remains to be determined. Recently, the cDNA of a second can be currently divided into two groups based on their general a-subunit (a2) was cloned, but its normal partner also is not yet structure and cellular distribution. One major group, which known ( 1). associates with the particulate fractions of cell homogenates, contains a subgroup of cell surface receptor guanylyl cyclases Particulateforms ofguanylyl cyclase (sea urchin spermatozoa, GC-A, GC-B, GC-C) that are acti- (a) Retinal guanylyl cyclases. Guanylyl cyclases with different vated by extracellular peptides, and appear to span the plasma functions are associated with various cells that exist in the ret- membrane once. An intracellular protein kinase-like domain ina (12, 13); at least one appears to play a key role in photo- on the amino-terminal side of the cyclase catalytic region is a transduction and is associated with rod outer segments. It has signature domain of this subgroup (Fig. 1). Intracellular pro- been suggested that a decrease in intracellular concentrations teins capable of binding Ca2" have been shown to regulate a of Ca 2+ activates a protein called recoverin that binds to and second subgroup ofguanylyl cyclases found associated with the activates this form of guanylyl cyclase (14, 15). The primary particulate fractions of mammalian retina, and the ciliary structure of the rod outer segment guanylyl cyclase has not yet membranes of the protozoans Tetrahymena pyriformis and been determined, and purification procedures have resulted in Paramecium tetraurelia (Table I). The primary amino acid apparently different proteins. One form purified from bovine sequence for a member of this subgroup is not yet known, and rod outer segments has an apparent molecular mass of 110- 1 5 kD ( 16), similar to the particulate forms of guanylyl cy- clase discussed later. The specific activity of the purified retinal Address correspondence to Stephen K.-F. Wong, Ph.D., University of enzyme ( 100-700 nmol cyclic GMP formed/min per mg pro- Texas, Southwestern Medical Center at Dallas, 5323 Harry Hines Bou- tein), however, is quite low when compared with other particu- levard, Room L5-218, Dallas, TX 75235-9050. Receivedfor publication 6 March 1992. 1. Abbreviations used in this paper: ANP, atrial natriuretic peptide; J. Clin. Invest. CFTR, cystic fibrosis transmembrane regulator; CNP, C-type natri- ©) The American Society for Clinical Investigation, Inc. uretic peptide; EDRF, endothelium-derived relaxation factor; EGF, 0021-9738/92/08/0299/07 $2.00 epithelial growth factor; GC, guanylyl cyclases; PDGF, platelet-derived Volume 90, August 1992, 299-305 growth factor; STa, heat-stable enterotoxins. Receptor Guanylyl Cyclases 299 Extracellular Table I. Different Forms of Guanylyl Cyclases Guanylyl cyclase Cellular form localization Regulatory molecules References Retinal GC Particulate Ca2+/recovenn (14, 15, 18) Tetrahymena Particulate Ca2+/calmodulin (20, 22) GC Paramecium GC Particulate Ca2+/calmodulin (21, 22) Sea urchin GC Particulate Egg peptides, (17, 23, 24) resact GC-A Particulate ANP, ATP (19, 25, 26, 46) GC-B Particulate CNP, ATP (28, 33) GC-C Particulate Heat-stable (30-32, 66) enterotoxins, ATP GC(.lw#,) Soluble Nitric oxide (5, 9, 60, 70) Nitro vasodilators GC(a ) ? ?(11) GC(a?,02) ? ? (10) raurelia ( 21) are distinct from the retinal guanylyl cyclases in that an increase in Ca2" to micromolar concentrations acti- vates them. The guanylyl cyclase from the cilia ofparamecium is involved in ciliary beating of the protozoa and it appears to be regulated by a voltage-gated inward Ca2" current (21). Guanylyl cyclases from both of these protozoans are regulated by calmodulin like Ca2l -binding modulator proteins, and the Intracellular nature of these regulatory proteins has been discussed in a pre- Figure 1. Schematic model for plasma membrane and heterodimeric vious review (22). forms of guanylyl cyclases. The plasma membrane form of guanylyl (c) Plasma membrane/receptor guanylyl cyclases. Sea ur- cyclase contains an extracellular ligand-binding region, a single chin sperm guanylyl cyclase has been shown to be a cell surface membrane-spanning domain, a protein kinase-like domain, and a receptor for a peptide (resact) secreted from sea urchin eggs catalytic domain at the carboxyl terminus. The heterodimeric form (23). This was the first plasma membrane form of guanylyl contains two distinct subunits that are linked intermolecular di- by cyclase to sulfide bonds. This form also contains an associated heme prosthetic purified apparent homogeneity ( 17) and its mRNA group. subsequently cloned (24). The sea urchin cDNA was then used to identify and isolate a mammalian cDNA encoding a gua- nylyl cyclase (GC-A) (25, 26), the first mammalian plasma membrane form of the enzyme to be cloned. GC-A was subse- late forms of guanylyl cyclase ( 17), and it is likely therefore quently shown to be a cell surface receptor for a heart-derived that either much of the enzyme in the retinal preparation is not peptide, atrial natriuretic peptide (ANP) (25, 27) (Table II). active, or that there are significant protein contaminants Subsequently, the mRNA for other apparent plasma mem- within the purified preparation. Like the plasma membrane brane forms of guanylyl cyclase were found (GC-B, GC-C) receptor forms discussed below,
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