Differential Activation of Cultured Neonatal Cardiomyocytes by Plasmalemmal Versus Intracellular G Protein-coupled Receptor 55

Yu, Justine; Deliu, Elena; Zhang, Xue-Quian; Hoffman, Nicholas E.; Carter, Rhonda L.; Grisanti, Laurel A.; Brailoiu, G. Cristina; Madesh, Muniswamy; Cheung, Joseph Y.; Force, Thomas; Abood, Mary E.; Koch, Walter J.; Tilley, Douglas G.; Brǎiloiu, Eugen

doi:10.1074/jbc.m113.456178

Cited by 37 publications

(43 citation statements)

References 75 publications

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“…We note that the significant effects of LPI observed in this study occurred at concentrations of 1 and 10 mM, which are well in the range of tissue concentrations that can be reached in pathophysiological states in vivo (Shen et al, 2001;Xiao et al, 2001;Sutphen et al, 2004;Ross, 2011) and largely similar to those promoting cellular effects in vitro (Falasca et al, 1995;Lauckner et al, 2008;Yu et al, 2013). Brain concentration of lipids, and implicitly, LPI, are difficult to evaluate due to limitations in extraction procedures, specificity, and rapid degradation.…”

Section: Functional Role Of Gpr55 In the Periaqueductal Graymentioning

confidence: 72%

“…We and others previously reported that LPI-induced activation of GPR55 is associated with Ca 21 signaling in neurons and other cell types (Lauckner et al, 2008;Pineiro and Falasca, 2012;Yu et al, 2013). Ca 21 responses in PAG neurons may differentially impact modulatory pain signals originating in this brain region.…”

Section: Discussionmentioning

confidence: 99%

“…1). We identified ML-193 as a GPR55 selective antagonist in a b-arrestin, high-throughput, high-content screening of 300,000 compounds (Heynen-Genel et al, 2010) and previously showed that at the concentration tested in the present study, ML-193 lacks any activity at L-type Ca 21 channels, inositol 1,4,5-trisphosphate receptors (IP 3 Rs), ryanodine receptors, and two-pore channels, whereas it completely antagonizes LPI-mediated Ca 21 responses (Yu et al, 2013). To further support the appropriateness of our tools, we evaluated the Ca 21 responses of GPR55-U2OS cells and untransfected U2OS cells to LPI and ML-193.…”

Section: Lpi Increases Intracellular Camentioning

confidence: 98%

“…Measurement of Membrane Potential. The relative changes in membrane potential of single neurons were evaluated using bis-(1,3-dibutylbarbituric acid) trimethine oxonol, DiBAC 4 (3) (Invitrogen), a slow response voltage-sensitive dye, as previously described (Yu et al, 2013;Deliu et al, 2014). Upon membrane hyperpolarization, the dye concentrates in the cell membrane, leading to a decrease in fluorescence intensity, whereas depolarization induces the sequestration of the dye into the cytosol, resulting in an increase of the fluorescence intensity.…”

Section: Methodsmentioning

confidence: 99%

“…This is not unusual because Ca 21 release from distinct stores has critical functional implications and the shape and amplitude of the Ca 21 signals also modulate distinct cellular functions (Rizzuto and Pozzan, 2006). Moreover, we previously reported that GPR55 stimulation can result in activation of distinct signaling cascades involving Ca 21 as a second messenger, which differentially impact membrane polarization (Yu et al, 2013).…”

Section: Functional Role Of Gpr55 In the Periaqueductal Graymentioning

confidence: 99%

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The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray

et al. 2015

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Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been explored. Using Ca 21 imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca 21 levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca 21 release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca 21 entry via P/Q-type of voltage-gated Ca 21 channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.

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Section: Functional Role Of Gpr55 In the Periaqueductal Graymentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Lpi Increases Intracellular Camentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Functional Role Of Gpr55 In the Periaqueductal Graymentioning

confidence: 99%

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The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray

et al. 2015

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GPCR Signaling from Intracellular Membranes

Jong¹,

Harmon²,

O’Malley³

2022

GPCRs as Therapeutic Targets

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l‐α‐Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK‐dependent pathway

Robertson-Gray

Walsh

Ryberg

et al. 2019

Pharmacology Res & Perspec

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The phospholipid l‐α‐lysophosphatidylinositol ( LPI ), an endogenous ligand for GPR 55, is elevated in patients with acute coronary syndrome, and a GPR 55 antagonist cannabidiol ( CBD ) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little is known about which ones are important in cardiomyocytes. In this study we explored whether activation of the Rho kinase/ ROCK /p38 MAPK pathway is responsible for LPI ‐induced extension of I/R injury. Using a high‐throughput screening method (dynamic mass redistribution; DMR ), mouse‐ and human‐induced pluripotent stem cell ( iPSC ) cardiomyocytes exposed to LPI were shown to exhibit a rapid, sustained, and concentration‐dependent (1 nmol L −1 ‐30 μmol L −1 ) cellular response. Y‐27632 ( ROCK inhibitor; 10 & 50 μmol L −1 ) and CBD (1 μmol L −1 ) both abolished the DMR response to LPI (10 μmol L −1 ). In murine iPSC cardiomyocytes, LPI ‐induced ROCK and p38 MAPK phosphorylation, both of which were prevented by Y‐27632 and CBD , but did not induce JNK activation or cleavage of caspase‐3. In hearts isolated from wild type ( WT ) mice subjected to 30 minutes global I/R, LPI (10 μmol L −1 ) administered via the coronary circulation increased infarct size when applied prior to ischemia onset, but not when given at the time of reperfusion. The exacerbation of tissue injury by LPI was not seen in hearts from GPR 55 −/− mice or in the presence of Y‐27632, confirming that injury is mediated via the GPR 55/ ROCK /p38 MAPK pathway. These findings suggest that raised levels of LPI in the vicinity of a developing infarct may worsen the outcome of AMI.

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Differential Activation of Cultured Neonatal Cardiomyocytes by Plasmalemmal Versus Intracellular G Protein-coupled Receptor 55

Cited by 37 publications

References 75 publications

The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray

The Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueductal Gray

GPCR Signaling from Intracellular Membranes

l‐α‐Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK‐dependent pathway

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