The Croonian Lecture, 1988 - Inositol lipids and calcium signalling

Abstract

The response of cells to many external stimuli requires a decoding process at the membrane to transduce information into intracellular messengers. A major decoding mechanism employed by a variety of hormones, neuro-transmitters and growth factors depends on the hydrolysis of a unique inositol lipid to generate two key second messengers, diacylglycerol and inositol 1,4,5-trisphosphate (Ins(1,4,5)P$_{3}$). Here I examine the second messenger function of Ins(1,4,5)P$_{3}$ in controlling the mobilization of calcium. We know most about how this messenger releases calcium from internal reservoirs but less is known concerning the entry of external calcium. One interesting possibility is that Ins(1,4,5)P$_{3}$ might function in conjunction with its metabolic product Ins(1,3,4,5)P$_{4}$ to control calcium entry through a mechanism employing a region of the endoplasmic reticulum as a halfway house during the transfer of calcium from outside the cell into the cytoplasm. The endoplasmic reticulum interposed between the plasma membrane and the cytosol may function as a capacitor to insure against the cell being flooded with external calcium. When stimulated, cells often display remarkably uniform oscillations in intracellular calcium. At least two oscillatory patterns have been recognized suggesting the existence of separate mechanisms both of which may depend upon Ins(1,4,5)P$_{3}$. In one mechanism, oscillations may be driven by periodic pulses of Ins(1,4,5)P$_{3}$ produced by receptors under negative feedback control of protein kinase C. The other oscillatory mechanism may depend upon Ins(1,4,5)P$_{3}$ unmasking a process of calcium-induced calcium release from the endoplasmic reticulum. The function of these calcium oscillations is still unknown. This Ins(1,4,5)P$_{3}$/calcium signalling system is put to many uses during the life history of a cell. It first occurs in immature oocytes, it functions during fertilization and there is an intriguing possibility that it might play a role in pattern formation during early development. Fully differentiated cells continue to employ this highly versatile system for regulating a host of functions including contraction, secretion and metabolism.