Background:The mechanism and significance of phosphoinositide metabolism during heart stress stimulations are not clear. Results: Norepinephrine and angiotensin II increase cardiac phosphatidylinositol 4,5-bisphosphate levels via an enhanced interaction between phosphatidylinositol 4-kinase III and PKC, which correlate with a maintained systolic function. Conclusion: Cardiac phosphoinositide turnover is enhanced. Significance: A novel mechanism of phosphoinositide metabolism is described for modulation of cardiac function.
Transient receptor potential vanilloid type 1 (TRPV1) is a nonselective cation channel activated by capsaicin, low pH, and noxious heat and plays a key role in nociception. Understanding mechanisms for functional modulation of TRPV1 has important implications. One characteristic of TRPV1 is that channel activity induced by either capsaicin or other activators can be sensitized or modulated by factors involving different cell signaling mechanisms. In this study, we describe a novel mechanism for the modulation of TRPV1 function: TRPV1 function is modulated by 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonic acid (DIDS) and its analogs. We found that, in rat dorsal root ganglion neurons, although DIDS did not induce the activation of TRPV1 per se but drastically increased the TRPV1 currents induced by either capsaicin or low pH. DIDS also blocked the tachyphylaxis of the low pH-induced TRPV1 currents. 4-Acetamido-4Ј-isothiocyanatostilbene-2,2Ј-disulfonic acid (SITS), a DIDS analog, failed to enhance the capsaicin-evoked TRPV1 current but increased the low pH-evoked TRPV1 currents, with an effect comparable with that of DIDS. SITS also blocked the low pH-induced tachyphylaxis. DIDS also potentiated the currents of TRPV1 channels expressed in human embryonic kidney 293 cells, with an effect of left-shifting the concentrationresponse curve of the capsaicin-induced TRPV1 currents. This study demonstrates that DIDS and SITS, traditionally used chloride channel blockers, can modify TRPV1 channel function in an agonist-dependent manner. The results provide new input for understanding TRPV1 modulation and developing new modulators of TRPV1 function.
Many neurotransmitters activate G-protein-gated inwardly rectifying K+ (Kir3) channels by stimulating G-protein-coupled receptors. However, in native systems, only receptors coupled to pertussis-toxin (PTX)-sensitive G proteins (Gi/Go) have been shown to be able to activate Kir3 channels through the βγ subunits of G proteins (Gβγ), whereas activation of receptors coupled to PTX-insensitive G proteins such as Gq or Gs do not activate Kir3 channels. The question remains as to how signaling specificity is achieved and what are its key determinants. In this study, we have used the Xenopus oocyte expression system to investigate specific activation of Kir3 channels by heterotrimeric G proteins. We have demonstrated the activation of Kir3.4 channels by agonist stimulation of non-PTX-sensitive G proteins under conditions of Gα subunit overexpression. We present evidence to suggest a key role for the coupling efficiency of Gα subunits in determining the specificity of Gβγ signaling to the channel.
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