Cell signalling

# 1.3 Most receptors are on the cell surface

Water-soluble signalling molecules cannot cross the membrane lipid bilayer, but bind to specific receptors embedded in the plasma membrane. The receptors have an extracellular domain that binds the signalling molecule, a hydrophobic transmembrane domain and an intracellular domain.

Binding of a ligand induces a conformational change in the receptor, in particular that of its intracellular region. It is this conformational change that activates a relay of intracellular signalling molecules, ultimately bringing about the appropriate cellular response represented in Figure 2.

Receptors can be classified structurally into single-pass transmembrane receptors (with one extracellular, one transmembrane and one intracellular region) and multipass transmembrane receptors.However, in terms of their signal transduction characteristics, it is easier to distinguish four groups of receptors (Figure 4).

Figure 4 The four major classes of membrane receptors: (a) ion-channel receptors; (b) 7-helix transmembrane receptors (7TM receptors); (c) receptors with intrinsic enzymatic activity (RIEA); (d) enzyme-associated receptors (recruiter receptors).

1. Receptors that also serve as the effector For example, one type of acetylcholine receptor is also an ion channel, and belongs to a family of receptors called ion-channel receptors. In response to acetylcholine, these receptors allow the passage of specific ions, thereby effecting changes in the membrane potential of a cell. Acetylcholine receptors are extremely important in the transmission of electrical signals between excitable cells.

2. 7-helix transmembrane receptors 7TM receptors possess seven membrane-spanning regions, an N-terminal extracellular region and a C-terminal intracellular tail. The mechanism of activation of most 7TM receptors involves coupling to G proteins, and in this case they are also called G protein-coupled receptors (GPCRs). Adrenalin receptors are examples of GPCRs.

3. Receptors whose intracellular tail contains an enzymatic domain, which are known as receptors with intrinsic enzymatic activity (RIEA) This group includes the receptor tyrosine kinases, involved in the response to many growth factors.

4. Receptors that require association with cytosolic or membrane-bound proteins with enzymatic activity for signalling These receptors do not have intrinsic enzymatic activity, and have been referred to as enzyme-associated receptors or recruiter receptors (although, strictly speaking, both GPCRs and receptors with intrinsic enzymatic activity also function by recruiting cytosolic signalling molecules, as you will see in Section 3.3).

From an evolutionary perspective (Figure 5), 7TM receptors are of ancient origin and to date have been found in all eukaryotic genomes that have been sequenced, including yeast (a type of 7TM receptor mediates the yeast mating response described in Section 1.2 and Figure 1). Receptors with intrinsic enzymatic activity and many recruiter receptors are found in C. elegans, D. melanogaster and chordates but not yeast, whereas some recruiter receptors, such as T cell receptors that mediate immune responses, are specific to vertebrates (others such as cytokine receptors are specific to chordates, including all vertebrates and some invertebrates such as the sea-squirt).

Figure 5 Evolutionary origins of plasma membrane receptors. Receptor families are presented in order of their presumed appearance during evolution. (RIEA = receptors with intrinsic enzymatic activity.)

In addition to the four groups of cell-surface receptors shown in Figure 4, another group of receptors function as DNA-binding molecules, and thus regulate gene transcription (these are called receptors with intrinsic transcriptional activity; do not confuse with RIEAs). Some of these receptors are on the cell surface, but most are intracellular (Section 3.5), and require ready access of the ligand to the intracellular compartment.

What sort of ligand might act on an intracellular receptor?

## Answer

Signalling molecules that can readily diffuse through the cell membrane. These include lipid-soluble compounds such as steroid hormones, and small diffusible molecules such as NO.

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