EDITORIAL FOCUS
-Adrenergic receptors and Ca2+.
Focus on "
-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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ARTICLE |
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
3-adrenergic receptor gene
polymorphism has been linked to obesity and early onset
non-insulin-dependent diabetes mellitus, and
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
-adrenergic receptor activation, tuning the amount of energy
production or wasting by mitochondria (8). Brown fat
adipocytes express primarily
1- and
3-adrenergic receptors, which mediate their effects
through distinct signaling pathways.
3-Adrenergic
receptors elevate cellular cAMP, increase the rate of lipolysis, and
upregulate UCP1 expression (3, 6, 7), whereas
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
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
3- and
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
-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
-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
-and
-adrenergic signaling pathway contributions.
First, the authors confirm that isoproterenol does weakly activate
-adrenergic receptors in brown fat adipocytes. However, the
isoproterenol responses were severely attenuated in the presence of
general (propranolol or bupranolol)
-adrenergic receptor
antagonists, suggesting the requirement for
-adrenergic receptor
activation as well. No intracellular Ca2+ responses were
elicited by the
3-adrenergic receptor-specific agonist
BRL-37344, confirming the need for both
- and
3-adrenergic receptor activation. BRL-37344 was,
however, able to potentiate the effects of low doses of the
-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
-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.
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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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Am J Physiol Cell Physiol 282(5):C980-C981
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