G<sub>i</sub> proteins mediate activation of the canonical hedgehog pathway in the myocardium

Carbe, Christian; Cheng, Lan; Addya, Sankar; Gold, Jessica I.; Gao, Erhe; Koch, Walter J.; Riobó, Natalia A.

doi:10.1152/ajpheart.00166.2014

Cited by 23 publications

(22 citation statements)

References 32 publications

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“…As discussed in more detail below (46), this structural homology couples with the observation that activating mutations in Smo occur at sites that appear to stabilize the inactive state of class A GPCRs to suggest that the 7TM region of Smo is likely to undergo GPCR-like conformational changes during its activity cycle (45). Such a conformational cycle would also be consistent with the ability of Smo to signal through G-proteins in certain circumstances (47)(48)(49)(50)(51)(52).…”

Section: Smoothened: 7tm Regionmentioning

confidence: 64%

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

McCabe¹,

Leahy

2015

Journal of Biological Chemistry

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A general aim of studies of signal transduction is to identify mediators of specific signals, order them into pathways, and understand the nature of interactions between individual components and how these interactions alter pathway behavior. Despite years of intensive study and its central importance to animal development and human health, our understanding of the Hedgehog (Hh) signaling pathway remains riddled with gaps, question marks, assumptions, and poorly understood connections. In particular, understanding how interactions between Hh and Patched (Ptc), a 12-pass integral membrane protein, lead to modulation of the function of Smoothened (Smo), a 7-pass integral membrane protein, has defied standard biochemical characterization. Recent structural and biochemical characterizations of Smoothened domains have begun to unlock this riddle, however, and lay the groundwork for improved cancer therapies. Members of the Hedgehog (Hh)3 family of secreted signaling proteins are present in most metazoans and owe their name to the effects that loss of Hh function has on Drosophila embryos, which lose their normal segmented pattern and develop a uniform coat of bristles reminiscent of the coats of hedgehogs (1). As presaged by this phenotype, Hh proteins mediate essential tissue patterning events during many stages of animal development (2), and abnormal Hh function is associated with birth defects and cancer (3). Hh proteins are also involved in tissue maintenance and wound repair in adult animals (4). Hh proteins achieve their patterning effects by functioning as classical morphogens (5). That is, Hh proteins form gradients of decreasing concentration from sites of secretion and induce concentration-dependent differentiation of distinct cell types (6, 7). As befits a morphogen, Hh expression, release, diffusion, and signal reception are tightly regulated by multiple factors (8).Classical and modern genetic techniques have identified several cell-surface proteins and glycans involved in receiving or modifying Hh signals (9). The core components of this process, conserved in all organisms known to have active Hh signaling, are Patched (Ptc) and Smoothened (Smo) (Fig. 1) (10 -13). Ptc functions upstream of Smo and has been genetically and biochemically defined as a primary component of the Hh receptor (14,15). Ptc is a 12-pass integral membrane protein with distant homology to bacterial resistance-nodulation-cell division (RND) transporters (16,17). Transmembrane helices 2-6 of Ptc are also homologous to sterol-sensing domains, which are found in diverse integral membrane proteins and regulate activity in response to levels of free cellular sterols (18). Smo is a member of the Frizzled family (class F) of G-protein coupled receptors (GPCRs) (19), and contains an N-terminal, ϳ14-kDa extracellular cysteine-rich domain (CRD) connected via a linker to 7 membrane-spanning helices (7TM) and an extended (ϳ200 amino acids, human; ϳ450 amino acids, Drosophila) C-terminal tail.Hh signaling responses are modulated by additional ce...

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Section: Smoothened: 7tm Regionmentioning

confidence: 64%

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

McCabe¹,

Leahy

2015

Journal of Biological Chemistry

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“…In vitro data were confirmed in transgenic mice with cardiomyocyte-inducible GiCT expression [37]. Transgenic GiCT mice showed specific reduction of Gli1 expression in the heart under basal conditions and failed to upregulate the Hh pathway upon ischemia and reperfusion injury [37]. This study characterizes the transcriptional response of cardiomyocytes to Shh and establishes a critical role for Smo coupling to Gi in Hh signaling in the normal and ischemic myocardium.…”

Section: Hedgehog In the Ischemic Heartmentioning

confidence: 79%

“…In addition, neonatal rat ventricular cardiomyocytes infected with an adenovirus encoding GiCT, a peptide that impairs receptor-Gi protein coupling, showed reduced activation of Hh targets. In vitro data were confirmed in transgenic mice with cardiomyocyte-inducible GiCT expression [37]. Transgenic GiCT mice showed specific reduction of Gli1 expression in the heart under basal conditions and failed to upregulate the Hh pathway upon ischemia and reperfusion injury [37].…”

Section: Hedgehog In the Ischemic Heartmentioning

confidence: 95%

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The Hedgehog Signaling Pathway in the Ischemic Heart, Brain, and Skeletal Muscle

Giarretta¹,

Gaetani²,

Tondi³

et al. 2018

Preprint

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Hedgehog (Hh) proteins are prototypical morphogens known to regulate epithelial/mesenchymal interactions during embryonic development. In addition to its pivotal role in embryogenesis, the Hh signaling pathway may be recapitulated in post-natal life in a number of physiological and pathological conditions, including ischemia. This review highlights the involvement of Hh signaling in ischemic tissue regeneration and angiogenesis, with particular attention to the heart, the brain, and the skeletal muscle. Updated information on the potential role of the Hh pathway as a therapeutic target in ischemic condition is also presented.

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“…GLI-dependent and -independent Hh signaling coexist in cells that have primary cilia, mainly cells in interphase or quiescent, like cardiomyocytes. We previously reported that SMO/G i protein coupling mediates up-regulation of canonical Hh signaling in response to ischemia and reperfusion injury, using animals with Tet-Off controlled cardiomyocyte-specific expression of a G i inhibitory peptide (the C-terminal domain of the G␣ i2 subunit) (G i CT/TTA mice) (12,13). In addition, we found that SMO activation rapidly reduces cAMP levels elevated in response to ␤ 2 -adrenergic receptor stimulation with isoproterenol (ISO) in cardiomyocytes in a G i protein-depen-dent manner (12).…”

Section: Smo (Smoothened) the Central Transducer Of Hedgehog Signalimentioning

confidence: 99%

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

Cheng¹,

Al‐Owais

Covarrubias

et al. 2018

Journal of Biological Chemistry

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SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric G proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GCT/TTA mice, in which G signaling is impaired, suggesting that the effect of SMO is mediated by G proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by G proteins regulates K currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias.

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G_i proteins mediate activation of the canonical hedgehog pathway in the myocardium

Cited by 23 publications

References 32 publications

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

The Hedgehog Signaling Pathway in the Ischemic Heart, Brain, and Skeletal Muscle

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

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Gi proteins mediate activation of the canonical hedgehog pathway in the myocardium

Cited by 23 publications

References 32 publications

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle

The Hedgehog Signaling Pathway in the Ischemic Heart, Brain, and Skeletal Muscle

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

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G_i proteins mediate activation of the canonical hedgehog pathway in the myocardium