EDITORIAL FOCUS
beta -Adrenergic receptors and Ca2+.
Focus on "beta -Adrenergic potentiation of endoplasmic reticulum Ca2+ release in brown fat cells"

Gerda E. Breitwieser

Department of Biology, Syracuse University, Syracuse, New York 13244


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BROWN FAT ADIPOCYTES are distinguished by a unique capacity to uncouple mitochondrial respiration and dissipate energy as heat, a process termed thermogenesis or nonshivering heat production. Thermogenesis plays a key role in small mammals during recovery from hibernation and in the maintenance of body temperature in the cold. Interest in the biology and regulation of adipose tissue has undergone a resurgence in recent years because of a potential involvement in regulation of metabolic rate and, hence, of obesity (1). Transgenic mice with reduced amounts of brown fat develop obesity, suggesting that brown fat is crucial to maintenance of nutritional homeostasis in rodents. The role of brown fat (or adipocytes in general) in regulation of metabolism in humans is less clear, although a human beta 3-adrenergic receptor gene polymorphism has been linked to obesity and early onset non-insulin-dependent diabetes mellitus, and beta 3-adrenergic agonists are being considered for treatment of obesity and insulin resistance (1, 7).

Catecholamines are key regulators of adipose tissue (3, 7), stimulating lipolysis and hydrolysis of triglycerides, and acutely regulating as well as increasing the expression of mitochondrial uncoupling protein (thermogenin or UCP1). UCP1 generates a nucleotide-inhibitable conductance pathway in the mitochondrial inner membrane, which is stimulated by the fatty acids generated upon beta -adrenergic receptor activation, tuning the amount of energy production or wasting by mitochondria (8). Brown fat adipocytes express primarily alpha 1- and beta 3-adrenergic receptors, which mediate their effects through distinct signaling pathways. beta 3-Adrenergic receptors elevate cellular cAMP, increase the rate of lipolysis, and upregulate UCP1 expression (3, 6, 7), whereas alpha 1-adrenergic receptors increase inositol 1,4,5-trisphosphate (IP3) and intracellular Ca2+ (4). There is some evidence for synergy between the two pathways, since elevated intracellular Ca2+ potentiates both the acute and long-term beta 3-mediated responses (3).

Leaver and Pappone, in the current article in focus (Ref. 4, see p. C1016 in this issue), explore the interactions between beta 3- and alpha 1-adrenergic receptors in rat brown adipocytes by focusing on the alterations in intracellular Ca2+ that result from pharmacological manipulations of the two signaling pathways. The beta -adrenergic agonist isoproterenol has been shown to increase intracellular Ca2+ in brown fat adipocytes, in addition to elevating cAMP. The authors begin their study by proposing two mechanisms for the isoproterenol-mediated effects: 1) cAMP regulation of UPC1 alters mitochondrial Ca2+ buffering or capacity, thereby increasing cytoplasmic Ca2+; or 2) as shown in other cell types, isoproterenol acts as a weak agonist at alpha -adrenergic receptors, thereby increasing intracellular Ca2+ via generation of IP3. What they discover is a third and more interesting mechanism: cAMP is able to potentiate Ca2+ release from IP3-sensitive stores in brown fat adipocytes, and the in vivo response to norepinephrine requires both alpha -and beta -adrenergic signaling pathway contributions.

First, the authors confirm that isoproterenol does weakly activate alpha -adrenergic receptors in brown fat adipocytes. However, the isoproterenol responses were severely attenuated in the presence of general (propranolol or bupranolol) beta -adrenergic receptor antagonists, suggesting the requirement for beta -adrenergic receptor activation as well. No intracellular Ca2+ responses were elicited by the beta 3-adrenergic receptor-specific agonist BRL-37344, confirming the need for both alpha - and beta 3-adrenergic receptor activation. BRL-37344 was, however, able to potentiate the effects of low doses of the alpha -adrenergic receptor-specific agonist phenylephrine, leading the authors to propose that cAMP is able to potentiate the responses to agents that increase intracellular Ca2+ via IP3.

Leaver and Pappone (4) generalize their findings by demonstrating that forskolin, a direct activator of adenylyl cyclase, can also potentiate intracellular Ca2+ responses. Furthermore, any receptor that increases IP3 and mediates Ca2+ release from thapsigargin-sensitive stores appears to be subject to cAMP-mediated potentiation, as they demonstrate with P2Y receptors. In light of the authors' findings that the cAMP-mediated increase in intracellular Ca2+ is specifically derived from IP3- and thapsigargin-sensitive Ca2+ stores, the intersection of the two signaling pathways may be the IP3 receptor itself.

cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of IP3 receptors has been demonstrated in numerous cell types, from hepatocytes to neurons, and can increase receptor affinity for IP3 and/or decrease the concentration of Ca2+ required for half-maximal stimulation (2, 5). Variable phosphorylation of IP3 receptors by cAMP-dependent PKA has been proposed as an explanation for the diverse abilities of distinct G protein-coupled receptors that signal through IP3 receptors to initiate and/or sustain intracellular Ca2+ oscillations (5). Those G protein-coupled receptors that activate only the primary pathway from Gq to phospholipase C generate high-frequency Ca2+ oscillations on a raised baseline of intracellular Ca2+, whereas G protein-coupled receptors that also facilitate cAMP-mediated IP3 receptor phosphorylation induce slow and sustained baseline spiking of intracellular Ca2+ (5). Interactions between IP3 and cAMP signaling pathways leading to variability in IP3 receptor phosphorylation have also been proposed to contribute to spatial regulation of Ca2+ signaling; PKA localization by AKAPs (A-kinase anchoring proteins) and localized IP3 production may contribute to the unique properties of Ca2+ release and/or signaling at distinct subcellular sites (2). Any or all of these mechanisms may contribute to the interactions of IP3 and cAMP signaling pathways, depending on the cell type under investigation.

Cross talk between diverse receptor-mediated signaling pathways has been characterized in many systems (2, 5). The origins may be trivial, i.e., activation of multiple receptor classes by "dirty" pharmacological agents, or fundamental to the complex mechanisms by which programs of cell regulation are activated. Brown fat adipocytes express beta -adrenergic receptors, which regulate various aspects of thermogenesis including lipolysis, triglyceride hydrolysis, and mitochondrial uncoupling through generation of cAMP. Leaver and Pappone (4) have now defined an additional role for cAMP in brown fat adipocytes, namely, potentiation of Ca2+ signaling stimulated by both adrenergic and nonadrenergic hormones. Determination of the exact molecular locus of signal integration represents the next experimental challenge.


    FOOTNOTES

Address for reprint requests and other correspondence: G. E. Breitwieser, Dept. of Biology, Syracuse Univ., 122 Lyman Hall, 108 College Place, Syracuse, NY 13244 (E-mail: gebreitw{at}syr.edu).

10.1152/ajpcell.00023.2002


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REFERENCES

1.   Arner, P. Genetic variance and lipolysis regulation: implications for obesity. Ann Med 33: 542-546, 2001[ISI][Medline].

2.   Bugrim, AE. Regulation of Ca2+ release by cAMP-dependent protein kinase. A mechanism for agonist-specific calcium signaling? Cell Calcium 25: 219-226, 1999[ISI][Medline].

3.   Collins, S, and Surwit R. The beta -adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 56: 309-328, 2001[Abstract/Free Full Text].

4.   Leaver, EV, and Pappone PA. beta -Adrenergic potentiation of endoplasmic reticulum Ca2+ release in brown fat cells. Am J Physiol Cell Physiol 282: C1016-C1024, 2002[Abstract/Free Full Text].

5.   LeBeau, AP, Yule DI, Groblewski GE, and Sneyd J. Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor. A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells. J Gen Physiol 113: 851-871, 1999[Abstract/Free Full Text].

6.   Lipworth, BJ. Clinical pharmacology of beta 3-adrenoreceptors. Br J Clin Pharmacol 42: 291-300, 1996[ISI][Medline].

7.   Lowell, BB, and Flier JS. Brown adipose tissue, beta 3-adrenergic receptors, and obesity. Annu Rev Med 48: 307-316, 1997[ISI][Medline].

8.   Nichols, DG. Mitochondrial uncoupling proteins. A history of UPC1. Biochem Soc Trans 29: 51-55, 2001.


Am J Physiol Cell Physiol 282(5):C980-C981
0363-6143/02 $5.00 Copyright © 2002 the American Physiological Society




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