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Cardiovascular Research 2007 75(4):631-633; doi:10.1016/j.cardiores.2007.07.005
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Copyright © 2007, European Society of Cardiology

Tight control of adrenal medulla catecholamine release by {alpha}2C-adrenergic receptors influences susceptibility to heart failure

Natalia Petrashevskaya* and Stephen B. Liggett

Cardiopulmonary Genomics Program, University of Maryland, School of Medicine, Baltimore, MD, United States

* Corresponding author. 20 Penn Street, HSF-II, Room S-112, Baltimore, MD 21201-1075. Tel.: +1 410 706 6256; fax: +1 410 706 6262. npetrash{at}medicine.umaryland.edu

Received 18 June 2007; accepted 13 July 2007


   Abstract
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 Abstract
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See article by Gilsbach et al. [3] (pages 728–737) in this issue.

β-Adrenergic receptors (βAR) expressed on myocytes act to increase cardiac contractility when activated by the catecholamines epinephrine and norepinephrine. In chronic heart failure, though, persistent activation leads to progressive loss of ventricular function [1,2]. The {alpha}2ARs, expressed on cardiac presynaptic nerves and adrenal medulla chromaffin cells, partially regulate catecholamine release. In this issue, Gilsbach et al. [3] show the critical role of the {alpha}2CAR subtype in epinephrine secretion from the adrenal gland in the context of heart failure.

Presynaptic norepinephrine release from cardiac sympathetic nerves is regulated by both {alpha}2A- and {alpha}2CAR [4,5]. Binding of released norepinephrine to these receptors acts to decrease subsequent release in a classic negative feedback fashion, providing a major mechanism for regulation of the response. The {alpha}2AAR appears to be particularly important for regulation of high frequency-stimulated norepinephrine release while the {alpha}2CAR primarily regulates low frequency-stimulated release. Epinephrine (and, to a lesser extent, norepinephrine) release from adrenal medulla chromaffin cells into the circulation is also under similar regulation by {alpha}2CARs expressed on these cells [6,7]. Gilsbach et al. [3] show that one half of the normal complement of {alpha}2CARs, as studied in heterozygous {alpha}2CAR knockout mice, is sufficient to cause a substantial increase in adrenal epinephrine release. Also, these mice were more susceptible to development of cardiac hypertrophy and failure under pressure overload (aortic banding) conditions. Given that this phenotype occurred with only a 50% decrease in {alpha}2CAR expression implies that there is little or no adrenal {alpha}2CAR receptor reserve. Indeed, most parameters followed a linear gene-dose response when {alpha}2C+/+, {alpha}2C+/–, and {alpha}2C–/– mice were studied. This points to the receptor itself (and its functional capacity) as a rate-limiting component in regulating catecholamine release. Potentially, any process that disrupts this pathway (via alterations in expression or function of the receptor, G-protein, effector, or regulating kinases) could have a significant effect on the risk or progression of heart failure, and this "nodal point" may be particularly amenable to therapeutic intervention [8].

These important results also point to the potential relevance of polymorphisms of the {alpha}2CAR gene in the human population. In the coding region of the {alpha}2CAR, an in-frame deletion of 12 nucleotides (from +964 to +975) results in the loss of the four amino acids Gly–Ala–Gly–Pro in the third intracellular loop of the receptor [9]. In transfected cells, this receptor, termed Del322-325, shows decreased high affinity agonist binding and minimal coupling to its cognate G-protein, G{alpha}i [9]. In those of African descent, Del322-325 is particularly prevalent, found in the homozygous form in ~15% of this population [10]; heterozygosity at this locus is ~45%. Since the polymorphic receptor is so dysfunctional, it is conceivable that heterozygous individuals express about one half of the functional complement of {alpha}2CAR (like the heterozygous {alpha}2CAR knockout mice) and thus may be susceptible to cardiac sequelae. In addition to this coding polymorphism, the intronless {alpha}2CAR gene has a number of polymorphisms in the promoter, 5'UTR and 3'UTR [10]. These are found in various combinations, termed haplotypes, in the human population (Fig. 1). The frequencies of the 24 haplotypes identified vary from ~1% to 60% in one of three ethnic populations [10]. In whole-gene transfection experiments, expression of {alpha}2CAR protein or mRNA varied by as much as ~2-fold. A number of these haplotypes do not contain the Gly–Ala–Gly–Pro deletion. However, the effects of the 5'- and 3'-flanking regions within these haplotypes on expression likely represent physiologically important variants of the {alpha}2CAR, because we now know that a ~50% decrease in expression is sufficient to promote pathologic events in vivo.


Figure 1
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  		Fig. 1 Localization of the {alpha}2CAR polymorphisms and their organization within haplotypes. The approximate position of each polymorphism within the intronless gene is shown as vertical lines. The location in the table is by nucleotide and is relative to the ATG of the initiator codon. The frequencies of the given haplotype are given in % for the indicated ethnic group. AD, African descent; ED, European descent; AsD, Asian descent. *, not applicable because of the presence of the deletion at +1483 to +1503.

 
There are several potential limitations in extrapolating the results from the study by Gilsbach et al. [3] in mice to heart failure susceptibility or progression in humans. A complete delineation of the relative levels of expression of the {alpha}2AR subtypes and their functional roles in catecholamine release from the human adrenal medulla is lacking. In addition, the "sensitivity" of the human heart to the alterations in adrenal-secreted epinephrine, or presynaptic norepinephrine release, imposed by a decrease in functional {alpha}2CAR is not known. However, the current results in mice clearly demonstrate this tight connection and justify the consideration of heterozygous polymorphisms of the {alpha}2CAR as cardiovascular risk factors or disease modifiers. To further complicate extrapolation to humans, we now know that there are functional polymorphisms of the {alpha}2AAR [11,12] as well as of the β2AR [13,14], the latter receptor also being expressed on presynaptic cardiac sympathetic nerves and influencing catecholamine release in a positive feedback manner. Finally, {alpha}2A- and {alpha}2CARs form homo- and heterodimers, as assessed by resonance energy transfer and co-immunoprecipitation methods [15]. It appears that the heterodimer complex acts as a signaling unit with unique properties [15]. The loss of one subtype can thus potentially alter the relative ratios of homodimers to heterodimers, which undoubtedly has a complex effect on cellular responses to epinephrine. Finally, it is intriguing that a hormone (epinephrine) that has effects on distal organs via the circulation has a local (as compared to a distant, or systemic-based) control mechanism. Nevertheless, the current results strongly indicate a tight control of epinephrine release by adrenal medullar {alpha}2CARs. This level of control has implications for polymorphisms with moderate phenotypes and heterozygosity and for drug development. In the latter case, minor modification of {alpha}2CAR function, which might be obtained with well-tolerated, low-dose, subtype-specific, agents (or gene therapies), seems to be a valid approach for new therapies.


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 Abstract
 References
 

  1. Liggett S.B. β-adrenergic receptors in the failing heart: the good, the bad, and the unknown. J Clin Invest (2001) 107:947–948.[Web of Science][Medline]
  2. Brodde O.E., Bruck H., Leineweber K. Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci (2006) 100:323–337.[CrossRef][Web of Science][Medline]
  3. Gilsbach R., Brede M., Beetz N., Moura E., Muthig V., Gerstner C., et al. Heterozygous {alpha}2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction. Cardiovasc Res (2007) 75:728–737.[Abstract/Free Full Text]
  4. Hein L., Altman J.D., Kobilka B.K. Two functionally distinct {alpha}2-adrenergic receptors regulate sympathetic neurotransmission. Nature (1999) 402:181–184.[CrossRef][Medline]
  5. Brede M., Philipp M., Knaus A., Muthig V., Hein L. Alpha2-adrenergic receptor subtypes ’ novel functions uncovered in gene-targeted mouse models. Biol Cell (2004) 96:343–348.[CrossRef][Web of Science][Medline]
  6. Brede M., Nagy G., Philipp M., Sorensen J.B., Lohse M.J., Hein L. Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol (2003) 17:1640–1646.[Abstract/Free Full Text]
  7. Lymperopoulos A., Rengo G., Funakoshi H., Eckhart A.D., Koch W.J. Adrenal GRK2 up-regulation mediates sympathetic overdrive in heart failure and its targeted inhibition represents a novel sympathetic therapy. Nat Med (2007) 13:315–323.[CrossRef][Web of Science][Medline]
  8. Liggett S.B. Long-distance affair with adrenal GRK2 hangs up heart failure. Nat Med (2007) 13:246–248.[CrossRef][Web of Science][Medline]
  9. Small K.M., Forbes S.L., Rahman F.F., Bridges K.M., Liggett S.B. A four amino acid deletion polymorphism in the third intracellular loop of the human {alpha}2C-adrenergic receptor confers impaired coupling to multiple effectors. J Biol Chem (2000) 275:23059–23064.[Abstract/Free Full Text]
  10. Small K.M., Mialet-Perez J., Seman C.A., Theiss C.T., Brown K.M., Liggett S.B. Polymorphisms of the cardiac presynaptic {alpha}2C adrenergic receptors: diverse intragenic variability with haplotype-specific functional effects. Proc Natl Acad Sci (2004) 101:13020–13025.[Abstract/Free Full Text]
  11. Small K.M., Forbes S.L., Brown K.M., Liggett S.B. An Asn to Lys polymorphism in the third intracellular loop of the human {alpha}2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling. J Biol Chem (2000) 275:38518–38523.[Abstract/Free Full Text]
  12. Small K.M., Brown K.M., Seman C.A., Theiss C.T., Liggett S.B. Complex haplotypes derived from noncoding polymorphisms of the intronless alpha2A-adrenergic gene diversify receptor expression. Proc Natl Acad Sci U S A (2006) 103:5472–5477.[Abstract/Free Full Text]
  13. Green S.A., Cole G., Jacinto M., Innis M., Liggett S.B. A polymorphism of the human β2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. J Biol Chem (1993) 268:23116–23121.[Abstract/Free Full Text]
  14. Drysdale C.M., McGraw D.W., Stack C.B., Stephens J.C., Judson R.S., Nandabalan K., et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci U S A (2000) 97:10483–10488.[Abstract/Free Full Text]
  15. Small K.M., Schwarb M.R., Glinka C., Theiss C.T., Brown K.M., Seman C.A., et al. Alpha2A- and alpha2C-adrenergic receptors form homo- and heterodimers: the heterodimeric state impairs agonist-promoted GRK phosphorylation and beta-arrestin recruitment. Biochem (2006) 45:4760–4767.[CrossRef][Web of Science][Medline]

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