Biophysical Journal 55: 769-778 (1989)
© 1989 the Biophysical Society

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mason, R P Articles by Herbette, L G Search for Related Content PubMed PubMed Citation Articles by Mason, R P Articles by Herbette, L G

Partitioning and location of Bay K 8644, 1,4-dihydropyridine calcium channel agonist, in model and biological membranes.

Department of Biochemistry, University of Connecticut Health Center, Farmington 06032.

ABSTRACT

Several lines of evidence suggest that nonspecific drug interaction with the lipid bilayer plays an important role in subsequent recognition and binding to specific receptor sites in the membrane. The interaction of Bay K 8644, a 1,4-dihydropyridine (DHP) calcium channel agonist, with model and biological membranes was examined at the molecular level using small angle x-ray diffraction. Nonspecific drug partitioning into the membrane was examined by radiochemical assay. Nonspecific binding characteristics of [3H] Bay K 8644 were determined in both dipalmitoyl phosphatidylcholine (DPPC) vesicles above and below their thermal phase transition (Tm) and rabbit skeletal muscle light sarcoplasmic reticulum (LSR). In DPPC, the partition coefficient, Kp, was 14,000 above the Tm (55 degrees C) versus 160 in the gel phase (2 degrees C). The Kp determined in LSR membranes was 10,700. These values for both DPPC and LSR membranes can be compared with Kp = 290 in the traditional octanol/buffer system. Using small-angle x-ray diffraction, the equilibrium position of the electron-dense trifluoromethyl group of Bay K 8644 in DPPC (above Tm) and purified cardiac sarcolemmal (CSL) lipid bilayers was determined to be consistently located within the region of the first few methylene segments of the fatty acyl chains of these membranes. This position is similar to that observed for the DHP calcium channel antagonists nimodipine and Bay P 8857. We suggest this particular membrane location defines a region of local drug concentration and plane for lateral diffusion to a common receptor site. Below the DPPC membrane Tm, Bay K 8644 was shown to be excluded from this energetically favored position into the interbilayer water space. Heating the DPPC bilayer above the Tm (55 degrees C) showed that this exclusion was reversible and indicates that drug-membrane interaction is dependent on the bilayer physical state. The absence of any specific protein binding sites in these systems allows us to ascertain the potentially important role that the bulk lipid phase may play in the molecular mechanism of DHP binding to the specific receptor site associated with the calcium channel.

This article has been cited by other articles:

				R. P. Mason, M. F. Walter, C. A. Day, and R. F. Jacob Active Metabolite of Atorvastatin Inhibits Membrane Cholesterol Domain Formation by an Antioxidant Mechanism J. Biol. Chem., April 7, 2006; 281(14): 9337 - 9345. [Abstract] [Full Text] [PDF]

				R. P. Mason, R. F. Jacob, M. F. Walter, P. E. Mason, N. A. Avdulov, S. V. Chochina, U. Igbavboa, and W. G. Wood Distribution and Fluidizing Action of Soluble and Aggregated Amyloid beta -Peptide in Rat Synaptic Plasma Membranes J. Biol. Chem., June 25, 1999; 274(26): 18801 - 18807. [Abstract] [Full Text] [PDF]