Inhibitory Effect of Fluvastatin on Lysophosphatidylcholine-Induced Nonselective Cation Current in Guinea Pig Ventricular Myocytes

Authors:
  • YSYuichi Suzuki
    Yuichi Suzuki
  • YWYasuhide Watanabe
    Yasuhide Watanabe
  • TIToshiyuki Ishibashi
    Toshiyuki Ishibashi
  • KYKeiko Yokoyama
    Keiko Yokoyama
  • YMYukio Maruyama
    Yukio Maruyama
  • JKJunko Kimura
    Junko Kimura
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Abstract
GH3 cells show spontaneous activity characterized by bursts of action potentials and oscillations in [Ca2+]i. This activity is modulated by the activation of exogenously expressed opioid receptors. In GH3 cells expressing only μ receptors (GH3MOR cells), the μ receptor-specific ligand [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited spontaneous Ca2+ signaling by the inhibition of voltage-gated Ca2+ channels, activation of inward-rectifying K+ channels, and inhibition of adenylyl cyclase. In contrast, in cells expressing both μ and δ receptors (GH3MORDOR cells), DAMGO had an excitatory effect on Ca2+ signaling that was mediated by phospholipase C and release of Ca2+ from intracellular stores. The excitatory effect of DAMGO was also inhibited by pretreatment with pertussis toxin. Despite the excitatory effect on Ca2+ signaling, DAMGO inhibited Ca2+ channels and activated inward-rectifying K+ channels in GH3MORDOR cells, although to a lesser extent than in GH3MOR cells. Long-term treatment with the δ receptor-specific ligand [d-Pen2,d-Pen5]-enkephalin reduced the excitatory effect of DAMGO in the majority of GH3MORDOR cells and restored the inhibitory response to DAMGO in some cells. The inhibitory effect of somatostatin on Ca2+ signaling was not different in GH3MORDOR versus GH3MOR cells. These results indicate that interaction between μ- and δ-opioid receptors causes a change in the functional response to μ ligands, possibly by the formation of a μ/δ heterodimer with distinct functional properties.

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