Organization of β-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes

Shcherbakova, Olga G.; Hurt, Carl M.; Xiang, Yang; Dell’Acqua, Mark L.; Zhang, Qi; Tsien, Richard W.; Kobilka, Brian K.

doi:10.1083/jcb.200604167

Cited by 93 publications

(115 citation statements)

References 55 publications

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“…The reason for the clustering pattern of protein expression is unknown but is likely to be related to its role in the regulation of heart function. It was recently shown that the ␤ 1 -adrenergic receptor is enriched at sites of sympathetic nerve synapses in cardiomyocytes (33). Interestingly, we also observed enriched GPR22 protein expression in the highly innervated cells of the sinoatrial node and atrioventricular node in rat hearts (data not shown).…”

Section: Discussionsupporting

confidence: 56%

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Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor

Adams¹,

Wang²,

Davis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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G protein-coupled receptors (GPCRs) play an essential role in the regulation of cardiovascular function. Therapeutic modulation of GPCRs has proven to be beneficial in the treatment of human heart disease. Myocardial “orphan” GPCRs, for which the natural ligand is unknown, represent potential novel therapeutic targets for the treatment of heart disease. Here, we describe the expression pattern, signaling pathways, and possible physiological role of the orphan GPR22. GPR22 mRNA analysis revealed a highly restricted expression pattern, with remarkably abundant and selective expression in the brain and heart of humans and rodents. In the heart, GPR22 mRNA was determined to be expressed in all chambers and was comparable with transcript levels of the β1-adrenergic receptor as assessed by Taqman PCR. GPR22 protein expression in cardiac myocytes and coronary arteries was demonstrated in the rat heart by immunohistochemistry. When transfected into HEK-293 cells, GPR22 coupled constitutively to Gi/Go, resulting in the inhibition of adenyl cyclase. No constitutive coupling to Gs or Gq was observed. Myocardial mRNA expression of GPR22 was dramatically reduced following aortic banding in mice, suggesting a possible role in response to the stress associated with increased afterload. The absence of detectable GPR22 mRNA expression in the hearts of GPR22−/− mice had no apparent effect on normal heart structure or function; however, these mice displayed increased susceptibility to functional decompensation following aortic banding. Thus, we described, for the first time, the expression pattern and signaling for GPR22 and identified a protective role for GPR22 in response to hemodynamic stress resulting from increased afterload.

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Section: Discussionsupporting

confidence: 56%

“…In situ hybidization probes were generated from the TOPO II-GPR22 (mouse) plasmid using the RiboProbe In Vitro Transcription Kit (Promega) following the manufacturer's instructions. Sense and antisense 33 …”

Section: Methodsmentioning

confidence: 99%

Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor

Adams¹,

Wang²,

Davis³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…In this model, both endogenous and exogenous SAP97 localizes exclusively at newly formed myocyte-myocyte contacts containing cadherins and connexin channels (1). Co-culture of cardiac myocytes and sympathetic neuronal cells has revealed another distinct localization of SAP97 at the contacts between nerve endings and myocytes, where the anchoring protein appears to be part of the ␤-adrenergic signaling complex (393). Taken together, these studies clearly indicate that SAP97 is not randomly distributed but is part of protein complexes involved in the formation of specialized membrane domains in cardiomyocytes.…”

Section: Figurementioning

confidence: 50%

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Balse

Steele

Abriel

et al. 2012

Physiological Reviews

109

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Cardiac myocytes are characterized by distinct structural and functional entities involved in the generation and transmission of the action potential and the excitation-contraction coupling process. Key to their function is the specific organization of ion channels and transporters to and within distinct membrane domains, which supports the anisotropic propagation of the depolarization wave. This review addresses the current knowledge on the molecular actors regulating the distinct trafficking and targeting mechanisms of ion channels in the highly polarized cardiac myocyte. In addition to ubiquitous mechanisms shared by other excitable cells, cardiac myocytes show unique specialization, illustrated by the molecular organization of myocyte-myocyte contacts, e.g., the intercalated disc and the gap junction. Many factors contribute to the specialization of the cardiac sarcolemma and the functional expression of cardiac ion channels, including various anchoring proteins, motors, small GTPases, membrane lipids, and cholesterol. The discovery of genetic defects in some of these actors, leading to complex cardiac disorders, emphasizes the importance of trafficking and targeting of ion channels to cardiac function. A major challenge in the field is to understand how these and other actors work together in intact myocytes to fine-tune ion channel expression and control cardiac excitability.

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“…Despite their sequence similarities, ␤ 1 AR does not behave like ␤ 2 AR following ligand binding. ␤ 1 AR internalizes at a higher rate in cardiomyocytes and does not relocalize away from contact sites with sympathetic ganglion neurons or out of caveolar fractions following ligand binding (36,37). Therefore, regulation of S-palmitoylation at the distal site by a specific subset of palmitoyltransferases could contribute to discrimination between these receptors.…”

Section: Discussion ␤ 1 Ar Is S-palmitoylated At Two Sites In Its Cytmentioning

confidence: 99%

Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor

Zuckerman

Hicks

Charron

et al. 2011

Journal of Biological Chemistry

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S-Palmitoylation of G protein-coupled receptors (GPCRs) is a prevalent modification, contributing to the regulation of receptor function. Despite its importance, the palmitoylation status of the ␤ 1 -adrenergic receptor, a GPCR critical for heart function, has never been determined. We report here that the ␤ 1 -adrenergic receptor is palmitoylated on three cysteine residues at two sites in the C-terminal tail. One site (proximal) is adjacent to the seventh transmembrane domain and is a consensus site for GPCRs, and the other (distal) is downstream. These sites are modified in different cellular compartments, and the distal palmitoylation site contributes to efficient internalization of the receptor following agonist stimulation. Using a bioorthogonal palmitate reporter to quantify palmitoylation accurately, we found that the rates of palmitate turnover at each site are dramatically different. Although palmitoylation at the proximal site is remarkably stable, palmitoylation at the distal site is rapidly turned over. This is the first report documenting differential dynamics of palmitoylation sites in a GPCR. Our results have important implications for function and regulation of the clinically important ␤ 1 -adrenergic receptor.

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Organization of β-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes

Cited by 93 publications

References 55 publications

Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor

Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor

Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes

Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor

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