The magnitude of signal amplification by ligand-induced receptor clustering

Abstract

Lateral mobility of plasma-membrane proteins is now documented for a variety of cell systems. Evidence is accumulating that the molecular clustering allowed by such mobility may be important in the transduction of information at the cell surface^1–7. Moreover, in a wide variety of systems, only a very small fraction of receptors need to be bound to induce a response^8,9, such as in the mast cell/basophil system where receptor clusters as small as dimers can induce a response¹⁰ and only three or four such dimers are necessary for local degranulation¹¹. As receptors are mobile, some clustering is expected even in the absence of ligand. As an approximate indication of the numbers involved, a consideration of constraints on translational entropy by spontaneous pair formation predicts¹² about 100 pairs on average for a cell with 500,000 receptors (typical of mast cells¹³), if a pair is defined as two receptors whose peripheries are within 5 Å This estimate need not present a problem as it can be reduced by several orders of magnitude by postulating orientational requirements, repulsive potentials and/or more stringent constraints on tanslational entropy. Moreover, some cell preparations do show a slow Ca²⁺-dependent background release² and this may, in fact, reflect spontaneous clustering and suggest that the control of activity is not stringent for those cells. An alternative view of the regulation of activity, however, which may have broad implications, is that receptors must be in proximity for some minimum amount of time for the transmission of biological information. This residency requirement may, for example, reflect the time required for the initiation of Ca²⁺ flow¹⁴ or for receptors to change conformation¹⁵ or for the pair to bind an integral membrane protein¹⁶. Whatever the origin, the quantitative predictions of the idea, which I develop here, suggest, for biologically relevant parameter values, an exceedingly sensitive control mechanism that can amplify the probability of an event by a factor of 10²⁰ or more.