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Cholesterol depletion modulates basal L-type Ca²⁺ current and abolishes its β-adrenergic enhancement in ventricular myocytes

¹Department of Physiology, Juntendo University School of Medicine, Tokyo, Japan; and ²Department of Physiology, New York Medical College, Valhalla, New York

Submitted 16 July 2007 ; accepted in final form 29 October 2007

Cholesterol is a primary constituent of the plasmalemma, including the lipid rafts/caveolae, where various G protein-coupled receptors colocalize with signaling proteins and channels. By manipulating cholesterol in rabbit and rat ventricular myocytes using methyl-β-cyclodextrin (MβCD), we studied the role of cholesterol in the modulation of L-type Ca²⁺ currents (I_Ca,L). MβCD was mainly dialyzed from BAPTA-containing pipette solution during whole cell clamp. In rabbit myocytes dialyzed with 30 mM MβCD for 10 min, a positive shift in membrane potential at half-maximal activation (V_0.5) from –8 to –2 mV developed and was associated with an increase in current density at positive potentials (42% at +20 mV vs. time-matched controls). Isoproterenol (ISO) increased I_Ca,L approximately threefold and caused a negative shift in V_0.5 in control cells, but it did not increase I_Ca,L in MβCD-treated myocytes, nor did it shift V_0.5. The effect of MβCD (10 or 30 mM) was concentration dependent: 30 mM MβCD suppressed the ISO-induced increase in I_Ca,L more effectively than 10 mM MβCD. MβCD dialysis also abolished the increase in I_Ca,L elicited by forskolin or dibutyryl cAMP, but not that elicited by (–)BAY K 8644. External application of MβCD-cholesterol complex to rat myocytes attenuated the MβCD-mediated inhibition of the ISO-induced increase of I_Ca,L. Biochemical analysis confirmed that the myocytes' cholesterol content was diminished by MβCD and increased by MβCD-cholesterol complex. Cholesterol thus appears to contribute to the regulation of basal I_Ca,L and β-adrenergic cAMP/PKA-mediated increases in I_Ca,L. We suggest that cholesterol affects the structural coupling between L-type Ca²⁺ channels and adjacent regulatory proteins.

lipid raft; adenosine 3',5'-cyclic monophosphate; protein kinase A; phosphorylation

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