Abstract:
BACKGROUND AND PURPOSE:Volume-regulated anion channels (VRACs) play an important role in cell-volume regulation. alpha(1)-Adrenoceptor stimulation by phenylephrine (PE) suppressed the hypotonic activation of VRAC current in mouse ventricular cells and regulatory volume decrease (RVD) was also absent in PE-treated cells. We examined whether the effects of alpha(1)-adrenoceptor stimuli on VRAC current were modulated by phosphatidylinositol signalling. EXPERIMENTAL APPROACH:Whole-cell patch-clamp method was used to record the hypotonicity-induced VRAC current in mouse ventricular cells. RVD was analyzed by videomicroscopic measurement of cell images. KEY RESULTS:The attenuation of VRAC current by PE was suppressed by alpha(1A)-adrenoceptor antagonists (prazosin and WB-4101), anti-G(q) protein antibody and a specific phosphoinositide-specific phospholipase C (PLC) inhibitor (U-73122), but not by antagonists for alpha(1B)-, alpha(1D)- or beta-adrenoceptor, or protein kinase C inhibitors. The inhibition of VRAC by PE was antagonized by intracellular excess phosphatidylinositol 4,5-bisphosphate (PIP(2)), while intracellular anti-PIP(2) antibody (PIP(2) Ab) inhibited the activation of VRAC currents. When cells were loaded with phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) with or without PIP(2) Ab, PE little affected the VRAC current. Extracellular m-3M3FBS (an activator of PLC) suppressed VRAC in the absence of PE, and this effect was reversed by intracellular excess PIP(2). CONCLUSIONS AND IMPLICATIONS:Our results indicate that the stimulation of alpha(1A)-adrenoceptors by PE inhibited the activation of cardiac VRAC current via PIP(3) depletion brought about by PLC-dependent reduction of membrane PIP(2) level.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Ichishima K,Yamamoto S,Iwamoto T,Ehara Tdoi
10.1111/j.1476-5381.2010.00896.xsubject
Has Abstractpub_date
2010-09-01 00:00:00pages
193-206issue
1eissn
0007-1188issn
1476-5381pii
BPH896journal_volume
161pub_type
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