Depolarisation induces rapid and transient formation of intracellular sphingosine‐1‐phosphate

Alemany, Regina; Kleuser, Burkhard; Ruwisch, Lars; Danneberg, Kerstin; Lass, Holger; Hashemi, Rozita; Spiegel, Sarah; Jakobs, Karl H.; Heringdorf, Dagmar Meyer zu

doi:10.1016/s0014-5793(01)03168-4

Cited by 41 publications

(26 citation statements)

References 36 publications

(89 reference statements)

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“…A more recent study demonstrated that membrane depolarization and influx of extracellular Ca 2ϩ increased cellular (PC12 and RINm5F cells) Sphk1-dependent formation of S1P. 15 The current study links these two independent findings to a concept in which downstream the stretch-induced depolarization and subsequent influx of extracellular Ca 2ϩ S1P (depolarization-dependently produced by Sphk1) translates these initial events into a release of Ca 2ϩ from intracellular stores, 10 combined with an activation of the Ca 2ϩ -sensitizing RhoA pathway. Consequently, genetic inhibition of Sphk1 by its dominant negative mutant resulted in significantly attenuated and delayed increases in Ca 2ϩ and only residual myogenic vasoconstrictions.…”

Section: Discussionmentioning

confidence: 97%

“…The activity of the S1P-generating enzyme Sphk1 is increased by membrane depolarization and activation of voltage-gated Ca 2ϩ channels. 15 Both effects are known to be essential for MRs, 13 leading us to hypothesize that Sphk1 is a part of the pressure-induced signaling cascade. To study a potential role of Sphk1 for this transduction pathway, we used a new transfection model to overexpress Sphk1 16 and its dominant negative mutant hSK-G82D 17 in VSMCs of isolated RAs.…”

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confidence: 99%

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Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase

et al. 2003

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase

et al. 2003

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“…Several reasons may contribute as to why: (1) it potentially allows for localization to plasma membrane microdomains (eg, caveolae), which are enriched with its substrate, sphingosine, and offer the opportunity to cluster with other S1P-related signaling components; (2) localization to the membrane would be a necessary prerequisite for the previously described export of S1P and/or Sk1 20 ; and (3) exposure of Sk1 to alterations in electric potential, which may modulate its activity, 21 can only occur at the plasma membrane. We therefore aimed to bypass the translocation deficiency of the Sk1 S225A mutant by the addition of a myristoylation/palmitylation motif that acts as a membrane anchor (mp-Sk1 S225A ).…”

Section: Discussionmentioning

confidence: 99%

The Phosphorylation Motif at Serine 225 Governs the Localization and Function of Sphingosine Kinase 1 in Resistance Arteries

Lidington

Peter²,

Meißner³

et al. 2009

ATVB

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Objective-The purpose of this study was to characterize a phosphorylation motif at serine 225 as a molecular switch that regulates the pressure-dependent activation of sphingosine kinase 1 (Sk1) in resistance artery smooth muscle cells. Methods and Results-In isolated hamster gracilis muscle resistance arteries, pressure-dependent activation/translocation of Sk1 by ERK1/2 was critically dependent on its serine 225 phosphorylation site. Specifically, expression of Sk1 S225A reduced resting and myogenic tone, resting Ca 2ϩ , pressure-induced Ca 2ϩ elevations, and Ca 2ϩ sensitivity. The lack of function of the Sk1 S225A mutant could not be entirely overcome by forced localization to the plasma membrane via a myristoylation/palmitylation motif; the membrane anchor also significantly inhibited the function of the wild-type Sk1 enzyme. In both cases, Ca 2ϩ sensitivity and myogenic tone were attenuated, whereas Ca 2ϩ handling was normalized/ enhanced. These discrete effects are consistent with cell surface receptor-mediated effects (Ca 2ϩ sensitivity) and intracellular effects of S1P (Ca 2ϩ handling). Accordingly, S1P 2 receptor inhibition (1mol/L JTE013) attenuated myogenic tone without effect on Ca 2ϩ . Conclusions-Translocation and precise subcellular positioning of Sk1 is essential for full Sk1 function; and two distinct S1P pools, proposed to be intra-and extracellular, contribute to the maintenance of vascular tone. Key Words: myogenic vasoconstriction Ⅲ signal transduction Ⅲ transfection Ⅲ ERK1/2 Ⅲ sphingosine-1-phosphate W hen transmural pressure increases, resistance arteries undergo myogenic vasoconstriction, an intrinsic response of vascular smooth muscle cells (VSMCs) to elevated mechanical load. 1 Under normal physiological conditions, myogenic vasoconstriction acts as a critical element in the regulation of tissue perfusion, which also leads to further augmentation of systemic blood pressure. Several cellular events and signaling mediators have been proposed to control myogenic vasoconstriction 2 ; we have recently identified sphingosine kinase 1 (Sk1) and its product, sphingosine-1-phosphate (S1P), as mandatory components of the pressureinduced signaling cascade. 3 Although Sk1 is activated in response to elevated transmural pressure, the mechanisms through which its product, S1P, act are only partially described. S1P can activate signaling cascades as both an intracellular second messenger and as an extracellular receptor ligand (via the S1P-specific membrane receptors S1P 1 , S1P 3 and S1P 5 ). 4 Although the intracellular targets of S1P are not well described, S1P receptor stimulation via extracellular S1P is known to activate RhoA/Rho kinase 3,5 and stimulate the generation of reactive oxygen species, 6 purportedly via the small GTPase Rac. Both of these signaling events possess a modulatory role in the control of the Ca 2ϩ sensitivity of the VSMC contractile apparatus, with important functional consequences with respect to myogenic vasoconstriction. 3,6 In the absence of stimulation, Sk1 posses...

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“…Initially, resting tone did not differ between the 2 groups ( Figure 5B). Following depolarization, which activates Sk1, 20 H208A ( Figure 5C). H208A in resistance arteries had no effect on myogenic vasoconstriction (B), diameter/Ca 2ϩ relationship (C), or the dose-response curve (D) to exogenous S1P (for graphs B through D, nϭ5 for control and nϭ8 for SPP1 H208A groups).…”

Section: Spp1 Wt Antagonizes Enhanced Vascular Responsiveness In Sk1 mentioning

confidence: 99%

“…This may represent a methodological limitation whereby measurement of S1P-induced increases in Ca sensitivity are compromised by the intrinsic sensitivity of Sk1 to depolarizing stimuli. The depolarizing conditions required to clamp intracellular Ca 2ϩ (via extracellular Ca 2ϩ ) may activate Sk1 20 and stimulate the release of S1P (or activate other Ca 2ϩ -sensitizing mechanisms) such that measurement occurs under conditions of near-maximal Ca 2ϩ sensitivity. This is in accordance with one of our previous observations, where exogenously applied S1P also failed to left shift the Ca 2ϩ -sensitivity curve under these specific experimental conditions.…”

Section: ϫ8mentioning

confidence: 99%

Role of Sphingosine-1-Phosphate Phosphohydrolase 1 in the Regulation of Resistance Artery Tone

Peter

Lidington²,

Harada³

et al. 2008

Circulation Research

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Abstract-Sphingosine-1-phosphate (S1P), which mediates pleiotropic actions within the vascular system, is a prominent regulator of microvascular tone. By virtue of its S1P-degrading function, we hypothesized that S1P-phosphohydrolase 1 (SPP1) is an important regulator of tone in resistance arteries. Hamster gracilis muscle resistance arteries express mRNA encoding SPP1. Overexpression of SPP1 (via transfection of a SPP1 wt ) reduced resting tone, Ca 2ϩ sensitivity, and myogenic vasoconstriction, whereas reduced SPP1 expression (antisense oligonucleotides) yielded the opposite effects. Expression of a phosphatase-dead mutant of SPP1 (SPP1 H208A ) had no effect on any parameter tested, suggesting that catalytic activity of SPP1 is critical. The enhanced myogenic tone that follows overexpression of S1P-generating enzyme sphingosine kinase 1 (Sk1 wt ) was functionally antagonized by coexpression with SPP1 wt but not SPP1 H208A . SPP1 modulated vasoconstriction in response to 1 to 100 nmol/L exogenous S1P, a concentration range that was characterized as S1P 2 -dependent, based on the effect of S1P 2 inhibition by antisense oligonucleotides and 1 mol/L JTE013. Inhibition of the cystic fibrosis transmembrane regulator (CFTR) (1) restored S1P responses that were attenuated by SPP1 wt overexpression; (2) enhanced myogenic vasoconstriction; but (3) had no effect on noradrenaline responses. We conclude that SPP1 is an endogenous regulator of resistance artery tone that functionally antagonizes the vascular effects of both Sk1 wt and S1P 2 receptor activation. SPP1 accesses extracellular S1P pools in a manner dependent on a functional CFTR transport protein. Our study assigns important roles to both SPP1 and CFTR in the physiological regulation of vascular tone, which influences both tissue perfusion and systemic blood pressure. Key Words: Ca 2ϩ sensitization Ⅲ signal transduction Ⅲ transfection Ⅲ vascular smooth muscle Ⅲ myogenic response Ⅲ cystic fibrosis transmembrane regulator T he bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) is a potent regulator of diverse biological processes, acting both as an intracellular second messenger and as an extracellular receptor ligand. Intracellular S1P (ie, second messenger) has been shown to mediate mitogenic/antiapoptotic 1 and Ca 2ϩ -mobilizing responses, 2 although the mechanisms controlling the latter remain undefined. As an extracellular receptor ligand, S1P can activate small GTPases (eg, RhoA and Rac), phospholipase C and adenylate cyclase via five distinct, G protein-coupled S1P receptors (S1P 1-5 ) (formerly known as EDG family receptors 3 ). Growing evidence supports an important role for S1P in the development and homeostasis of the vascular system, 4 -6 in the pathogenesis of vascular diseases, 7 and in the regulation of acute vascular responses. 8 Our laboratory has recently identified the S1P-generating enzyme sphingosine kinase 1 (Sk1) as a vascular smooth muscle cell (SMC) signaling component necessary for myogenic vasoconstriction in resistance arter...

show abstract

Depolarisation induces rapid and transient formation of intracellular sphingosine‐1‐phosphate

Cited by 41 publications

References 36 publications

Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase

Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase

The Phosphorylation Motif at Serine 225 Governs the Localization and Function of Sphingosine Kinase 1 in Resistance Arteries

Role of Sphingosine-1-Phosphate Phosphohydrolase 1 in the Regulation of Resistance Artery Tone

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