Heterotrimeric C proteins: Organizers of transmembrane signals

Hundreds of chemical and physical signals constantly bombard the surface of all cells. Some of these do not enter the cell but, instead, bind to receptors at the cell surface and initiate a flow of information that moves to the cell interior. The receptors for many hormones (such as catecholamines, gonadotropins, parathyroid hormone, and glucagon), odorants, and light span the membrane seven times (reviewed by Dohlman et al., 1991). Stimulation of these receptors activates a group of coupling proteins (called G proteins because they bind GTP) that regulate a variety of enzymes and ion channels. The target enzymes or ion channels are called effectors because changes in their activity cause the changes in ionic composition or in second messenger levels (such as cAMP or inositol phosphate levels) that ultimately lead to the cellular response. Every eukaryotic cell contains receptors for many kinds of chemical and/or physical signals, many different types of G proteins, and many effectors, each with multiple subtypes. A cell can only respond to those signals for which it has a receptor, but the specificitywith which the receptor interacts with the coupling proteins (the G proteins) defines the range of responses that a cell is able to make. Receptors are highly selective for their ligands. If a receptor can interact with only one subtype of G protein that can, in turn, activate only one type of effector, the response will be very focused. In contrast, if a receptor can interact with several G proteins, each of which can interact with more than one effector, the response would be expected to be spread over several pathways. As will be d iscussed below, a cell may respond to some signals with a very defined set of actions, but may respond to others less specifically. Similarly, a ligand that gives a focused response in one cell may cause a pleiotypic response in another. Over the last decade, there has been enormous progress in defining the elements that are involved in transmembrane signaling. A very large number of receptors have been cloned, characterized, and subdivided into families. Four subfamilies of G protein (~ subunits have been defined, and multiple G protein 13 and y subunits have been identified. We now know that effectors often come in several subtypes, each with different regulatory properties. What is still mysterious is exactly what determines specificity of the response of a cell to an extracellular stimulus. What is the grammar that controls the interpretation of signals? In this review, I will summarize some features of the structure and function of mammalian G protein subunits, then discuss how the elements of the cellular language may be ordered and weighted to allow the cell to respond properly to the message.