Premium
FLA 365 as an inhibitor of ryanodine receptors and L‐type Ca 2+ channels in arterial myocytes
Author(s) -
Ostrovskaya Olga,
Goyal Ravi,
McAllister Claire,
Hume Joseph R,
Pessah Isaac N,
Wilson Sean M
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1114-a
Subject(s) - ryanodine receptor , chemistry , ryanodine receptor 2 , endoplasmic reticulum , myocyte , biophysics , medicine , pharmacology , endocrinology , biochemistry , biology
Ryanodine (RY) is a highly selective ryanodine receptor (RyR) blocker, but RY binding is dependent on RyR opening. In whole‐cell studies, RY binding can lock the RyR in an open‐conductance state, short‐circuiting the sarcoplasmic reticulum (SR). This restricts studies of InsP 3 receptor (InsP 3 R) activity. Other RyR blockers also have non‐selective effects that also limit their utility. FLA 365 ([2,6‐dichloro‐4‐dimethyl‐aminophenyl] isopropylamine) blocks RyR elicited Ca 2+ increases in skeletal and cardiac muscle, yet its actions on smooth muscle are unknown. Canine pulmonary arterial smooth muscle cells (PASMCs) express both RyRs and InsP 3 Rs; thus, we tested the ability of FLA 365 (FLA) to block RyR and InsP 3 R elicited Ca 2+ release by imaging fura‐2 loaded PASMCs. Acute exposure to 10 mM caffeine, a selective RyR activator, induced Ca 2+ increases that were significantly reduced by 20 μM FLA, which was reversible. 10–100 μM FLA 365 reduced Ba 2+ currents through L‐type Ca 2+ channels in patch voltage‐clamp studies, similar to phenylalkylamines. 10 μM 5‐HT, which activates InsP 3 Rs, induced Ca 2+ increases of equivalent amplitude in the absence or presence of FLA. Thus, FLA blocks RyRs and L‐type Ca 2+ channels with limited impact on InsP 3 R signaling in PASMCs. NIH P20RR15518 from NCRR & HL49254 (JRH), PO1ES11269 & 2PO AR17605 (INP), HL10476, AI55462 & UM faculty fellowship (SMW).