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Negative interactions and feedback regulations are required for transient cellular response.

ABSTRACT: Signal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activation nature of downstream signaling molecules. The factors which we have investigated are loops (feed forward and feedback loops), cross-talk of signal transduction pathways, and the change in the concentration of the signaling molecules. Based on our results we conclude that among these factors feedback loop and the cross-talks which directly inhibit the target protein dominantly controls the transient cellular response.

SUBMITTER: Mobashir M

PROVIDER: S-EPMC3893651 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Negative interactions and feedback regulations are required for transient cellular response.

Mobashir Mohammad M Madhusudhan Thati T Isermann Berend B Beyer Tilo T Schraven Burkhart B

Scientific reports 20140116

Signal transduction is a process required to conduct information from a receptor to the nucleus. This process is vital for the control of cellular function and fate. The dynamics of signaling activation and inhibition determine processes such as apoptosis, proliferation, and differentiation. Thus, it is important to understand the factors modulating transient and sustained response. To address this question, by applying mathematical approach we have studied the factors which can alter the activa ...[more]

PMID: 24430195

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Project description:OBJECTIVE:Several physiological stimuli activate smooth muscle cell (SMC) GqPCRs (Gq protein-coupled receptors) to cause vasoconstriction. As a protective mechanism against excessive vasoconstriction, SMC GqPCR stimulation invokes endothelial cell vasodilatory signaling. Whether Ca2+ influx in endothelial cells contributes to the regulation of GqPCR-induced vasoconstriction remains unknown. Ca2+ influx through TRPV4 (transient receptor potential vanilloid 4) channels is a key regulator of endothelium-dependent vasodilation. We hypothesized that SMC GqPCR stimulation engages endothelial TRPV4 channels to limit vasoconstriction. APPROACH AND RESULTS:Using high-speed confocal microscopy to record unitary Ca2+ influx events through TRPV4 channels (TRPV4 sparklets), we report that activation of SMC ?1ARs (alpha1-adrenergic receptors) with phenylephrine or thromboxane A2 receptors with U46619 stimulated TRPV4 sparklets in the native endothelium from mesenteric arteries. Activation of endothelial TRPV4 channels did not require an increase in Ca2+ as indicated by the lack of effect of L-type Ca2+ channel activator or chelator of intracellular Ca2+ EGTA-AM. However, gap junction communication between SMCs and endothelial cells was required for phenylephrine activation or U46619 activation of endothelial TRPV4 channels. Lowering inositol 1,4,5-trisphosphate levels with phospholipase C inhibitor or lithium chloride suppressed phenylephrine activation of endothelial TRPV4 sparklets. Moreover, uncaging inositol 1,4,5-trisphosphate profoundly increased TRPV4 sparklet activity. In pressurized arteries, phenylephrine-induced vasoconstriction was followed by a slow, TRPV4-dependent vasodilation, reflecting activation of negative regulatory mechanism. Consistent with these data, phenylephrine induced a significantly higher increase in blood pressure in TRPV4-/- mice. CONCLUSIONS:These results demonstrate that SMC GqPCR stimulation triggers inositol 1,4,5-trisphosphate-dependent activation of endothelial TRPV4 channels to limit vasoconstriction.

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Negative interactions and feedback regulations are required for transient cellular response.

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Negative interactions and feedback regulations are required for transient cellular response.

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