The concept of a changing receptor concentration: implications for the theory of drug action

Drugs are considered to produce their effects on biological tissues either by altering some physical property of cells or by interacting with specific cellular components, called receptors. Most drugs and endogenous neurotransmitters act on highly selective receptors located on the outer surface membrane of cells. These receptors were believed, until recently, to be stationary on the cell surface and to be present in unvarying numbers. Consequently, most early theorists modeled the drug-receptor interaction on the basis of stationary and static receptor molecules. The substantial advances in our understanding of drug action based on these models have partly justified this view. However, recent electron microscopic studies have revealed the presence of structures, including "coated" pits and vesicles, that appear to provide a mechanism by which cell surface receptors might be internalized in a process of endocytosis. The precise intracellular fate of these internalized receptors is unknown, but based on present understanding, it seems reasonable to believe that some are destroyed intracellularly whereas others are recycled to the cell surface. The importance of such processes to pharmacologic theory is a new awareness of a cellular pathway that is capable of internalizing drugs, receptors, or both. The implications of such a process to the theory of drug action extends to some unexplained drug phenomena such as down regulation, drug tolerance, tachyphyllaxis, and partial agonism. We present herein the theoretical framework for a model of drug action that incorporates the possibility of receptor internalization and subsequent degradation, recycling, or replacement.     

Control and oscillation in ligand receptor interactions according to the law of mass action

The law of mass action is almost universally applied to interactions of both endogenous ligands and drugs with their specific receptors and results in the familiar hyperbolic equilibrium binding curve of bound (y) vs free (z) concentrations. Whereas the concentration of a drug molecule is governed by its pharmacokinetic properties and, possibly, by intrinsic control mechanisms, natural ligands are certainly controlled since their concentrations normally remain within specific limits. This paper represents a further study of control of this kinetic process in a model based on ligand production (rate F), first-order elimination (rate constant E) and a feedback function of occupancy, phi(y), that modulates these. In the controlled situation the system equilibrium occurs at states called critical points (yc,zc) at which both dy/dt and dz/dt are simultaneously zero. There are only a finite number of such points along the hyperbolic binding curve and these may be either stable or unstable. The basal state is the normal operating point of the system and is necessarily stable; that is, perturbations producing states away from it will return in time to this point. We have previously shown that phi'(y) less than or equal to 0 is a sufficient condition for stability. Accordingly, for a continuous control curve, an adjacent critical point will be unstable, and have phi'(y) greater than 0. If the system coordinates get sufficiently close to such an unstable point there is propulsion to extreme states and loss of control. The distance between the stable and unstable points determines whether a dose (or release) of the ligand will be controlled or not. The current paper focuses on the geometrical properties of the binding and control curves and how these relate to the stability of critical points and the overall control of ligand doses. In particular we show how the magnitude of the (negative) slope of the control curve at the basal point affects the frequency of oscillation about the basal state. It is further shown that high frequency control results in lower receptor occupancy, a result that may explain desensitization.     

Phospholipid base exchange enzyme activity in sarcolemmal membranes from the heart of cardiomyopathic hamsters

The activity of phospholipid base exchange enzymes has been evaluated in cardiac sarcolemmal membranes from Syrian Golden hamsters and from a hamster strain (UM-X7.1) characterized by a genetic form of hypertrophic cardiomyopathy. No choline base exchange activity and only a little serine base exchange activity were detected, whereas the ethanolamine base exchange enzyme was found highly active in membranes from both strains. For this reason, the present study is focussed on the ethanolamine base exchange enzyme. The apparent Km for ethanolamine of ethanolamine base exchange enzyme from Syrian Golden membranes and from UM-X7.1 strain membranes are 18 and 32 μM, respectively. The specific activity of the sarcolemmal ethanolamine base exchange enzyme is lower in the UM-X7.1 strain than in Syrian Golden hamsters. The calcium-dependence of the enzyme appears different when the membranes from the two strains are compared. Indeed, after removal of the membrane-bound divalent cations, comparable activities are found in both membrane preparations, whereas, upon addition of Ca²⁺ to the incubation mixtures, the activity of the enzyme is enhanced in the membranes from Syrian Golden strain more than in those from UM-X7.1 strain. The cholesterol content of sarcolemmal membranes is higher in the cardiomyopathic strain than in the Syrian Golden hamsters. A possible relation between changes of the membrane lipid composition and of the ethanolamine base exchange activity is discussed.