Physiological mechanisms of signal termination in biological systems.

Studies on the regulation of cellular activity mainly focus on signal generation, but termination of signalling is an equally important factor, which prevents inappropriate activity. This paper reviews the mechanisms, which can cause termination of signalling, and provides examples that illustrate the importance of these processes. Inactivation of voltage-gated Na(+) channels and the photoactivated rhodopsin molecule is caused by rapid conformational rearrangements. Negative feedback can also contribute to the termination of signalling for various mechanisms, including plasma membrane ion channels or cAMP signal generation. In immune cells, the tyrosine-based inhibitory motif (ITIM)-containing molecules are essential negative regulatory components. Desensitization of G-protein-coupled receptors can occur with homologous and heterologous mechanisms, mediated by β-arrestin molecules and second messenger-induced kinases respectively. In NF-κB signalling, resynthetized IκB and other enzymes form negative feedback loops. GTPase-activating proteins are also dedicated to termination of signalling, because they can switch off the small G proteins by increasing their endogenous GTP hydrolysis. In many systems, signal termination is a result of a combined action of several different mechanisms, which underlines the importance of these processes.