cell signalling

cell signalling Even the simplest unicellular organisms detect and respond to changes in their environment, but it is in multicellular organisms that signalling mechanisms are most highly developed. The division of labour that allows cells to adopt such diverse and specialized functions as muscle contraction, defending the body from disease, and absorbing and then distributing essential nutrients, is possible only because the activities of all the cells within an organ or tissue are co-ordinated and the activities of every organ and tissue are orchestrated to meet the needs of the body as a whole. Long-distance communication is by means of nerves and circulating hormones; the principal function of many organs, notably the endocrine glands, is to facilitate such communication between organs.

Cells communicate with each other by means of an enormous diversity of signalling molecules. These molecules have traditionally been classified according to the distance over which they act.

Local communication between neighbouring cells is described as paracrine signalling. This includes direct physical contact between proteins expressed on the surface of adjacent cells; the release of short-acting messengers, like nitric oxide, whose ranges of action are limited by their rapid inactivation; and the chemical communication between neurons. This last is provided by synaptic messengers or neurotransmitters (e.g. acetylcholine), which are released from the terminal of a neuron into the specialized area of contact that it makes with another neuron or muscle; the synapse. Such messengers need to diffuse only a few millionths of a centimetre to reach their target and can thereby very specifically address only the tiniest part of the body, perhaps only one of the 100 000 spines on a single neuron from among the 100 000 million neurons in a human brain. Autocrine signalling, wherein cells respond to signalling molecules that they have themselves released, is often presented as another category of signalling mechanism, although it too describes local communication, but between similar cells. Another form of local communication is provided by gap junctions, which directly link the cytoplasm of certain cells and so allow the exchange both of ions and of small molecules between them. The co-ordinated contraction of the many individual fibres within a human heart, for example, depends upon them being linked by gap junctions.

At the opposite extreme are the pheromones released by one person and detected by another. In the middle of the distance range lies endocrine signalling, mediated by the hormones (e.g. insulin) released from specialized endocrine glands into the bloodstream, which delivers them to their targets. Hormones may thereby exert their effects on many different tissues (in the case of insulin, primarily the liver, muscle, and fat) and so evoke an appropriately co-ordinated physiological response from widely separated organs and tissues.

Receptors are the means by which each of the chemical messengers that mediate intercellular communication are detected and decoded. Some messengers (nitric oxide and the steroid hormones are examples) are sufficiently hydrophobic to pass through the lipid plasma membrane that surrounds every cell and so gain direct access to the intracellular receptor proteins through which they mediate their physiological effects. Most messengers, however, cannot pass directly through the lipid and instead exert their effects by binding to and activating receptors that span the plasma membrane. From both their functional and structural properties, these receptors can be grouped into distinct families. The first comprises those in which the receptor protein forms a channel that opens when the receptor binds its messenger and allows specific ions to flow across the plasma membrane. Such receptors are commonly responsible for the fastest forms of chemical communication between cells, and include the nicotinic receptors that mediate the voluntary control of skeletal muscle. A second family includes the many hundreds of receptors that regulate cellular activity by first causing activation of a G protein. These G proteins, which themselves comprise a large family of proteins, have an intrinsic timer that allows them to remain active for a period, typically several seconds, after the receptor has caused their activation. A single receptor with its messenger bound is thereby able to sustain the activation of many G proteins and so provide an amplification step in the signalling pathway. Such amplification at both this and later steps in these signalling pathways allows cells to be exquisitely sensitive to very low concentrations of circulating hormones. The active G proteins are responsible for relaying the signal onwards to the ultimate physiological response by regulating either the opening of ion channels or the activities of intracellular enzymes. The latter include the enzymes responsible for both the synthesis and degradation of the intracellular messengers (e.g. cyclic AMP) that serve as the currency for intracellular communication. Earl W. Sutherland, who received the Nobel Prize for Physiology or Medicine in 1971, was the first to recognize that, despite the plethora of extracellular messengers each recognized by a unique receptor, intracellular signalling was likely to use a far more limited repertoire of signalling molecules or second messengers. The idea that specific receptors are the antennae of a cell that are fine-tuned to respond to only very specific signals from the babble of signals to which a cell is exposed, and then direct them to a small range of intracellular messengers, remains the keystone of cell signalling. A third, and very much more diverse, grouping of receptors includes those that are capable of either directly phosphorylating certain tyrosine residues of specific proteins or else activating accessory proteins with that ability. After activation, these receptors (which include the insulin receptor) serve as molecular scaffolds around which additional signalling proteins can assemble to generate rather complex webs of intracellular signals, mediated by both small soluble messengers and specific interactions between proteins. These receptor tyrosine kinases and their relatives are commonly, though not exclusively, involved in controlling long-term aspects of cellular behaviour, such as cell growth or differentiation.

C. W. Taylor

See also calcium; hormones; membrane receptors; neurotransmitters.