Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin

Kompa, A.; Samuel, Chrishan S.; Summers, Roger J.

doi:10.1038/sj.bjp.0704922

Cited by 64 publications

(54 citation statements)

References 35 publications

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“…The involvement of G i /G o proteins in the RXFP1 response to relaxin has been reported previously (Kompa et al, 2002). In functional assays, PTX pretreatment significantly decreased the maximum inotropic and chronotropic responses to relaxin in rat isolated atria, without alteration of potency.…”

Section: Discussionsupporting

confidence: 73%

“…In addition, MAPK inhibitors were shown to decrease cAMP in THP-1 cells, suggesting that MAPK-mediated inhibition of phosphodiesterases is required to give sustained increases in cAMP (Bartsch et al, 2001). When taken together with little to no cAMP responses in other tissues (Palejwala et al, 1998;Kompa et al, 2002), this suggested that the involvement of cAMP in relaxin signaling was minimal. However, relaxin stimulation of either RXFP1 or RXFP2 receptors stably expressed in HEK293T cells (HEK-RXFP1 and HEK-RXFP2, respectively) resulted in clear increases in cAMP , and constitutively active mutants showed ligand-independent cAMP production (Hsu et al, 2000.…”

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confidence: 99%

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Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms

Halls¹,

Bathgate²,

Summers³

2006

Mol Pharmacol

122

176

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Two orphan leucine-rich repeat-containing G protein-coupled receptors were recently identified as targets for the relaxin family peptides relaxin and insulin-like peptide (INSL) 3. Human gene 2 relaxin is the cognate ligand for relaxin family peptide receptor (RXFP) 1, whereas INSL3 is the ligand for RXFP2. Constitutively active mutants of both receptors when expressed in human embryonic kidney (HEK) 293T cells signal through G␣ s to increase cAMP. However, recent studies using cells that endogenously express the receptors revealed greater complexity: cAMP accumulation after activation of RXFP1 involves a time-dependent biphasic pathway with a delayed phase involving phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) , whereas the RXFP2 response involves inhibition of adenylate cyclase via pertussis toxin-sensitive G proteins. The aim of this study was to compare and contrast the cAMP signaling pathways used by these two related receptors. In HEK293T cells stably transfected with RXFP1, preliminary studies confirmed the biphasic cAMP response, with an initial G␣ s component and a delayed response involving PI3K and PKC. This delayed pathway was dependent upon G-␤␥ subunits derived from G␣ i3 . An additional inhibitory pathway involving G␣ oB affecting cAMP accumulation was also identified. In HEK293T cells stably transfected with RXFP2, the cAMP response involved G␣ s and was modulated by inhibition mediated by G␣ oB and release of inhibitory G-␤␥ subunits. Thus, initially both RXFP1 and RXFP2 couple to G␣ s and an inhibitory G␣ oB pathway. Differences in cAMP accumulation stem from the ability of RXFP1 to recruit coupling to G␣ i3 , release G-␤␥ subunits and thus activate a delayed PI3K-PKC pathway to further increase cAMP accumulation.Relaxin is a two-chain peptide hormone that is structurally closely related to insulin. It belongs to the insulin-relaxin peptide family that includes the relaxins: human gene (H)1 (product of a gene duplication event in higher primates), H2 (major circulating form), and H3 (principally a neuropeptide); insulin; insulin-like growth factors I and II; and the relaxin/insulin-like factors INSL3, INSL4, INSL5, and INSL6. Although relaxin was first identified for its role in parturition in guinea pigs (Hisaw, 1926), it is now recognized as a hormone with pleiotropic effects. Relaxin has important functions in the heart, kidney, and brain in addition to roles in the regulation of nitric oxide production and neoangiogenesis (for review, see Bathgate et al., 2006). It is noteworthy that relaxin can also prevent the tissue remodeling observed in fibrosis with a conservation of endogenous tissue structure , and herein lies its potential as a therapeutic.Despite the length of time since the discovery of relaxin, its receptor remained elusive until the recent pairing of relaxin family peptides with two highly similar leucine-rich repeatcontaining GPCRs: LGR7 and LGR8 . LGR7 was subsequently identified as the relaxin receptor and LGR8 as the receptor for the related peptide ...

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Section: Discussionsupporting

confidence: 73%

mentioning

confidence: 99%

Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms

Halls¹,

Bathgate²,

Summers³

2006

Mol Pharmacol

122

176

View full text Add to dashboard Cite

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“…In most cases, RLX was also reported to be a positive inotropic agent on isolated atria or whole heart (17,55,58,98,110), although some investigators failed to observe this effect (102,103). Using the patch clamp technique on isolated left and right atrial myocytes from rats, Piedras-Renteria et al (84,85) reported that 50 or 100 ng/ml native rat RLX inhibited the transient and sustained outward potassium currents via cAMPdependent protein kinase and increased calcium entry via both L-and T-type calcium channels.…”

Section: Influence Of Rlx On the Heartmentioning

confidence: 99%

Emerging role of relaxin in renal and cardiovascular function

Conrad

Novak

2004

American Journal of Physiology-Regulatory, Integrative and Comp

136

113

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Conrad, Kirk P., and Jacqueline Novak. Emerging role of relaxin in renal and cardiovascular function. Am J Physiol Regul Integr Comp Physiol 287: R250 -R261, 2004; 10.1152/ajpregu.00672.2003.-Although traditionally associated with reproductive processes, relaxin is emerging as an important player in renal and cardiovascular function. Much of our recently acquired understanding of relaxin in this new context has arisen from studies of maternal renal and cardiovascular adaptations to pregnancy in rats where the hormone is turning out to be an important mediator. First, we highlight the influence of relaxin on renal hemodynamics and glomerular filtration rate, as well as on other peripheral circulations. Second, we discuss the effect of relaxin on both the steady and pulsatile systemic arterial load, as well as on the heart, in particular, coronary blood flow. Third, we consider the impact of the hormone on cultured endothelial and vascular smooth muscle cells. Fourth, we address the interaction of relaxin with renal and cardiac disease, as well as its role in angiogenesis. Finally, in Perspectives, we point out several key research questions in need of investigation that relate to a potential autocrine/paracrine role of relaxin in renal and cardiovascular tissues. Furthermore, on the basis of its potent vasodilatory and matrix-degrading attributes, we speculate about the therapeutic potential of relaxin in renal and cardiovascular diseases. pregnancy; kidney circulation; glomerular filtration; osmoregulation; peripheral circulation; systemic hemodynamics; vasodilation; arterial compliance; heart; myogenic reactivity; angiogenesis; relaxin receptors; matrix metalloproteinase; gelatinase; endothelin B receptor; nitric oxide; angiotensin II THE OBJECTIVE OF THIS REVIEW is to highlight the new and emerging roles of relaxin (RLX) in the renal and cardiovascular systems. Traditionally, RLX has been tied to reproductive processes during pregnancy, because most investigations conducted by reproductive biologists have dealt with the hormone in this context. The traditional sources of RLX have been reproductive tissues such as the corpus luteum of the ovary from which the hormone emanates and circulates during the luteal phase of the menstrual cycle and during pregnancy in women (95). Furthermore, there has been no well-established role in the male. However, the concept of a role for RLX in cardiovascular function actually has its antecedents early on in the history of RLX research, when Frederick L. Hisaw, who discovered the hormone (47, 113), noted that after administration of RLX to castrated monkeys, there were marked morphological changes in the endothelial cells of the endometrium consistent with hypertrophy and hyperplasia (48). The concept that RLX can affect blood vessel structure and function has since gained considerable support, particularly in the last decade. Much of our recently gained knowledge of RLX in this new light has arisen from studies of maternal renal and cardiovascular function in the gravid rat mo...

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“…Thus far, most research has focused on relaxin-mediated signaling events. Increases in cAMP have been observed in some target tissues and cell lines (Fei et al, 1990;Parsell et al, 1996) but not in others (Palejwala et al, 1998;Kompa et al, 2002). In addition, there is evidence for mitogen-activated protein kinase [extracellular signal-regulated kinase (Erk) 1/2] activation in particular cell types, which may occur with (Bartsch et al, 2001;Zhang et al, 2002) or without (Palejwala et al, 1998(Palejwala et al, , 2001) associated increases in cAMP.…”

mentioning

confidence: 99%

Comparison of Signaling Pathways Activated by the Relaxin Family Peptide Receptors, RXFP1 and RXFP2, Using Reporter Genes

Halls¹,

Bathgate²,

Summers³

2006

J Pharmacol Exp Ther

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The receptors for H2 relaxin and insulin-like peptide 3, relaxin family peptide receptor (RXFP) 1 and RXFP2, respectively, were recently identified, but their signaling pathways are not yet well characterized. Although previous work has suggested that cAMP is a major signaling pathway activated by these receptors, RXFP1 has also been shown to activate a number of other signaling proteins. To this end, we examined the effect of stimulation of RXFP1 and RXFP2 receptors [expressed in human embryonic kidney (HEK) 293T cells] with human relaxin family peptides on a number of transcription factor-response elements coupled to reporter genes. Hence, reporter gene activity measured by enzyme activity in the cell media is a measure of the activation of a particular signaling pathway. Eight reporter genes were tested at both receptors as a screen to identify other signaling pathways activated by RXFP1 and RXFP2. The cAMP-response element reporter was strongly activated by both receptors. This effect was enhanced by preincubation with pertussis toxin (PTX), suggesting that G s and inhibitory G i /G o proteins mediate this response. Only activation of RXFP1 inhibited nuclear factor B transcription, and this was reversed by PTX and the phosphoinositide-3-kinase inhibitor wortmannin. In addition, the glucocorticoid-response element was activated by RXFP1 but not by RXFP2 and was not activated in the parent HEK293T cells. Thus, the use of reporter genes enabled differences in signaling between these two receptors to be revealed and also threw light on the wide range of effects attributed to relaxin.The discovery of relaxin was originally based on its effects on the pubic ligament in guinea pigs (Hisaw, 1926) and led to the identification of its roles in parturition in many mammals and in implantation in humans (Hayes et al., 2004;Shirota et al., 2005). Research since has revealed a broader spectrum of physiological effects that are not solely based on actions within the reproductive system and include roles for relaxin in the cardiovascular system, collagen remodeling, wound healing, fibrosis prevention, and as a neuropeptide (for detailed review, see Bathgate et al., 2006a) .Relaxin is a two-chain peptide hormone that belongs to the insulin/relaxin peptide family. This family encompasses the relaxins: human gene 1 (H1) relaxin, H2 relaxin, and H3 relaxin; insulin; insulin-like growth factors I and II; and the insulin-like ( LGR7 and LGR8 were identified as the receptors for H2 relaxin INSL3 (Kumagai et al., 2002), respectively, and GPCR135 and GPCR142 were identified as the receptors for H3 relaxin (Liu et al., 2003b) and INSL5, respectively (Liu et al., 2004). Based on recent International

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Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin

Cited by 64 publications

References 35 publications

Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms

Relaxin Family Peptide Receptors RXFP1 and RXFP2 Modulate cAMP Signaling by Distinct Mechanisms

Emerging role of relaxin in renal and cardiovascular function

Comparison of Signaling Pathways Activated by the Relaxin Family Peptide Receptors, RXFP1 and RXFP2, Using Reporter Genes

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