Numerous transmembrane proteins characterized by the presence of multiple immunoglobulin domains in their extracellular regions constitute the immunoglobulin (Ig) superfamily of CAMs, or IgCAMs (for example, see NCAM in Figure 20-2). The Ig domain is a common protein domain, containing 70–110 residues, that was first identified in antibodies, the antigen-binding immunoglobulins (see Chapter 23), but has a much older evolutionary origin in CAMs. The human, D. melanogaster, and C. elegans genomes include about 765, 150, and 64 genes, respectively, that encode proteins containing Ig domains. Immunoglobulin domains are found in a wide variety of cell-surface proteins, including the T-cell receptors produced by lymphocytes and many proteins that take part in adhesive interactions. Among the IgCAMs are neural CAMs; intercellular CAMs (ICAMs), which function in the movement of leukocytes into tissues; and junction adhesion molecules (JAMs), which are present in tight junctions (see Figure 20-18b).

As their name implies, neural CAMs are of particular importance in neural tissues. One type, the NCAMs, primarily mediate homophilic interactions. First expressed during morphogenesis, NCAMs play an important role in the differentiation of muscle cells, glial cells, and neurons. Their role in cell adhesion has been directly demonstrated by the inhibition of adhesion with anti-NCAM antibodies. Numerous NCAM isoforms, encoded by a single gene, are generated by alternative mRNA splicing and by differences in glycosylation. Other neural CAMs (e.g., L1-CAM) are encoded by different genes. In humans, mutations in different parts of the L1-CAM gene cause various neuropathologies (e.g., mental retardation, congenital hydrocephalus, and spasticity).

An NCAM comprises an extracellular region with five Ig domains and two fibronectin type III domains, a single membrane-spanning segment, and a cytosolic segment that interacts with the cytoskeleton (see Figure 20-2). In contrast, the extracellular region of L1-CAM has six Ig domains and four fibronectin type III domains. As with cadherins, cis (intracellular) interactions and trans (intercellular) interactions probably play key roles in IgCAM-mediated adhesion (see Figure 20-3); however, adhesion mediated by IgCAMs is Ca²⁺ independent.