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(Circulation. 1996;94:602-603.)
© 1996 American Heart Association, Inc.

Articles

Multifunctional G Proteins

Searching for Functions in the Heart

Gary L. Stiles, MD

the Division of Cardiology, Duke University Medical Center, Durham, NC.

Correspondence to Gary L. Stiles, MD, Duke University Medical Center, Box 3444, 405 Sands Bldg, Research Dr, Durham, NC 27710.

Key Words: Editorials • proteins • heart failure • receptors, adrenergic, alpha • signal transduction

	Introduction

Top Introduction References

 
Regulation of cell signaling pathways in pathophysiological conditions, such as ischemia or congestive heart failure, has been studied intensively for many decades. Much has been learned concerning how various receptors, guanine nucleotide–binding proteins (G proteins), and effector molecules, such as adenylyl cyclase or phospholipase C (PLC), are modulated in disease states.¹ We have learned that receptors can be upregulated and downregulated, receptor–G protein coupling can be perturbed, the quantity of G proteins can be influenced, and the ability to generate second messengers can be enhanced or reduced.¹ At one level, the accompanying article is simply another in a long line of studies showing how a particular receptor system, namely, the ₁-adrenergic receptor (AR), can be quantitatively modulated in some forms of congestive heart failure, such as ischemic cardiomyopathy, whereas the ₁-AR in dilated cardiomyopathy is not quantitatively controlled. In addition, the activity of the G protein to which the ₁-AR couples appears to be regulated in a significant manner but by different mechanisms in ischemic versus dilated cardiomyopathy. If this were the whole story, I would not have much else to say and probably would not even suggest that you read the accompanying article. However, this is not the entire story; the G protein (G_h) being studied in this case is a fascinating molecule, and the role it plays in cell regulation remains enigmatic.

G_h is a large, 74-kD protein (the more common G proteins, such as _s and _i, which stimulate or inhibit adenylyl cyclase, are all in the 40- to 45-kD range) capable of specific coupling to ₁-ARs and can activate a 69-kD PLC.^{2 3} This signaling pathway is a common mechanism by which a hormone such as epinephrine can act to increase intracellular inositol phosphate and Ca²⁺.^{2 3} What makes G_h so fascinating is that in addition to the standard functions of G subunits, such as the ability to bind and hydrolyze GTP (GTPase activity) and activate effector systems such as PLC, it contains a separate and distinct enzyme activity, namely transglutaminase (TGase) activity.⁴

TGases are enzymes that catalyze the posttranslational modification of proteins by forming an amide bond between the -carboxamide group of glutamine residues of a protein with the primary amino groups of other compounds and proteins.⁵ This effectively cross-links proteins, which stabilizes their structure and makes them resistant to proteolysis.⁵ A variety of different TGases are known to exist, and their functions have been elucidated. The coagulator function XIIIa is a plasma TGase that acts on fibrin at the sites of coagulation to cross-link and stabilize the fibrin clot. In contrast, tissue TGases such as G_h are membrane-bound or cytosolic proteins that are present in a wide variety of tissues, but their function remains unknown.⁵ In 1987, the Greenberg laboratory was studying liver TGases and made the observation that GTP could bind to these enzymes and that when it did, the TGase activity was inhibited.⁶ This inhibition was reversible and calcium sensitive.⁶ Other tissue TGases were likewise modulated, but plasma TGases were not. In 1990, the Graham group identified a new G protein, named G_h, which specifically coupled to the ₁-AR in liver membranes and had an apparent molecular mass of 74 kD.² Subsequent work by Baek et al³ documented that G_h was the coupling protein intermediary between ₁-ARs and PLC. A fascinating article in Science (1994) demonstrated that the G_h protein was indeed a TGase similar in nature to tissue TGase II.⁴ That article went on to document that ₁-AR–mediated h-GTP binding and was able to enhance the inhibition of the TGase activity by GTP. This documented the multifunctional nature of this GTP-binding protein and the reciprocal regulation of the two pathways by GTP. Thus, in the G_h-GDP (basal state of G proteins) bound state, G_h will display TGase activity in membranes (and cytosol, as shown in the accompanying article). However, under the influence of agonists such as epinephrine, the ₁-AR becomes activated and mediates the exchange of GTP for GDP on h, thus turning off TGase II activity to a greater extent than seen with GTP alone. This inactivation of TGase II activity permits h-GTP to activate PLC, thus increasing inositol trisphosphate and Ca²⁺ within the cell. The GTPase activity of h will subsequently hydrolyze GTP to GDP, terminating its signal transduction activity and reactivating the TGase II activity. This is a very elegant reciprocal regulatory pathway. At present, the physiological role of the TGase II activity in cellular function or dysfunction remains totally unknown. However, suggestions have been made that the TGase II activity may be important in such diverse functions as cell growth, differentiation, and activation of other signaling molecules.^{7 8} Much work remains to be done on what role G_h plays in modulating heart function in both health and disease.

The accompanying article documents that the ₁-AR–h pathway is differentially modulated in ischemic versus dilated cardiomyopathy. The concept that the mechanisms underlying all heart failure are not the same is well entrenched in the literature. In ischemic cardiomyopathy, ₁-ARs are increased twofold, ₁-AR–h coupling is decreased while the quantity of G_h in membranes is increased, and the GTP-binding capacity and TGase II activity are decreased.⁹ In dilated cardiomyopathy, there are no quantitative changes in ₁-ARs, and ₁-AR–h coupling is not impaired. Quantitatively, G_h is markedly increased, whereas GTP binding and TGase II activity are decreased. The importance of these changes remains to be determined. Of greater significance than these specific findings is the possible dual role of G_h in regulating cellular function in the heart as well as other tissues. This coupling protein can flip between a signaling pathway and an enzyme pathway. What the TGase II activity is doing remains to be learned.

If these two pathways play a causative role in the promulgation of the downward spiral seen in congestive heart failure, then elucidation of how this comes about may lead to new therapeutic approaches. Clearly, new therapeutic modalities are desperately needed. If the changes reported in this article are effect and not cause, then at least a potential new regulatory pathway that needs to be studied has been uncovered and highlighted.

"This is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning."

Winston S. Churchill, November 10, 1942.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction References

 

1. Stiles GL. Adrenergic receptor responsiveness and congestive heart failure. Am J Cardiol.. 1991;67:136-170.
   
2. Im M-J, Riek RP, Graham RM. A novel guanine nucleotide-binding protein coupled to the ₁-adrenergic receptor. J Biol Chem.. 1990;265:18944-18951 and 18952-18960.[Abstract/Free Full Text]
   
3. Baek KJ, Das T, Gray C, Antar S, Murugesau G, Im M-J. Evidence that the Gh protein is a signal mediator from ₁-adrenoceptor to a phospholipase C. J Biol Chem.. 1993;268:27390-27397.[Abstract/Free Full Text]
   
4. Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono K, Im M-J, Graham RM. Gh: a GTP-binding protein with transglutaminase activity and receptor signalling function. Science.. 1994;264:1593-1596.[Abstract/Free Full Text]
   
5. Greenberg CS, Birckbieler PJ, Rice RH. Transglutaminases: multifunctional crosslinking enzymes that stabilize tissues. FASEB.. 1991;5:3071-3077.[Abstract]
   
6. Achynthan KE, Greenberg CS. Identification of a guanosine triphosphate-binding site on guinea pig liver transglutaminase: role of GTP and calcium ions in modulating activity. J Biol Chem.. 1987;262:1901-1906.[Abstract/Free Full Text]
   
7. Murtaugh MP, Mehta K, Johnson J, Meyers M, Juliano RL, Davis PJ. Induction of tissue transglutaminase in mouse peritoneal macrophages. J Biol Chem.. 1983;258:11074-11081.[Abstract/Free Full Text]
   
8. Cordella-Miele E, Miele L, Mukherjee AB. A novel transglutaminase-mediated post-translational modification of phospholipase A₂ dramatically increases its catalytic activity. J Biol Chem.. 1990;265:17180-17188.[Abstract/Free Full Text]
   
9. Hwang K-C, Gray CD, Sweet WE, Moravec CS, Im M-J. ₁-Adrenergic receptor coupling with G_h in the failing human heart. Circulation.. 1996;94:718-726.[Abstract/Free Full Text]
   

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