Febs Letters Volume 69, Number 1./Volume 70, Number 1./Master Index Volumes 61-70. [antikvár]

Volume 69, number 1 FEBS LETTERS October 1976 Hypotliesis RECEPTOR OCCUPANCY DOSE-RESPONSE CURVE SUGGESTS THAT PHOSPHATIDYL-INOSITOL BREAKDOWN MAY BE INTRINSIC TO THE MECHANISM OF THE MUSCARINIC CHOLINERGIC RECEPTOR Robert H. MICHELL, Shamshad S. JAFFERJI and Lynne M. JONES Department of Biochemistry, Univershy of Birmingham, P.O. Box 363, Birmingham BI5 2TT, U.K. Received 26 May 1976 Formation of cAMP has been characterised as an enzyme-catalysed reaction involved in the ampUfica-tion of the chemical signals which are detected by various types of cell surface receptors [1], but little progress has been made towards identification of analogous reactions linked to receptors which do not exert their effects through control of adenylate cyclase. In some cases such reactions may not exist (e.g. the nicotinic cholinergic receptor? [2]) but in others it seems more likely that they have simply eluded identification by the experiments done so far. In most investigations of receptor mechanisms emphasis has been placed on responses which are provoked maximally by low ('physiological') concentrations of agonists. We would like to suggest that it might be more appropriate to concentrate on those responses which occur at higher, so-called 'unphysiological', agonist concentrations. This is because with many agonists (particularly small molecules such as neurotransmitters) it is necessary for only a small proportion of the cell's large population of functionally equivalent receptors to interact with agonist in order to provoke a maximal 'physiological' response such as secretion or contraction. This is thought to be because activation of only this small fraction of the total receptor population is sufficient to raise the intracellular concentration of a second messenger such as cyclic AMP or Ca^* enough to stimulate the responsive enzyme(s) fully. High concentrations of agonists are, though, needed to bring about a maximum increase in the second messenger concentration. Thus, if the reaction which causes the change in concentration of a second messenger (for example, adenylate cyclase or the mechanism which opens cell-surface Ca^* gates) is directly controlled by the activated fraction of the receptor population then its dose-response curve will follow the receptor occupation curve, i.e. that describing the agonist—receptor interaction. In a cell responding to an agonist for. which there is a large population of spare receptors any reaction intrinsic to the mechanism which initiates amphfication of the message received by the receptor should therefore show a dose-response curve displaced to much higher agonist concentrations than are needed for the 'physiological' responses. This general idea arises naturally from receptor occupation theory; it has already been used effectively in explaining the observed behaviour of receptor systems which involve control of adenylate cyclase and in which maximum activation of adenylate cyclase requires far higher agonist concentrations than are needed for maximum activation of 'physiological' responses [3-5]. Furthermore, recent studies have shown that the concentration of receptors of a particular type can vary widely from tissue to tissue (and at different times in a single tissue), but that the dose—response relationship which describes the agonist-receptor interaction is essentially identical in all systems in which it is measured (e.g., refs. [6—8]). As a result of the differences in receptor concentration, cell responses which are not directly coupled to the receptor vary in agonist sensitivity from tissue to tissue. In contrast, it is to be expected that reactions closely coupled to the activated receptors would vary in maximum response from tissue to tissue, but should always show dose-response curves identical with the receptor occupation curve: this is the pattern seen North-Holland Publishing Company - Amsterdam 1