Intercellular Adhesion Molecule-5
The discovery of ICAM-5 was made by K. Mori and colleagues in 1987. Mice were immunized with the synaptic fractions of olfactory bulb neurons and a series of monoclonal antibodies was generated. One of the antibodies showed immunoreactivity exclusively with the telencephalon (Mori et al. 1987). The target molecule was named telencephalin. Further analysis with this antibody showed a somatodendritic distribution, specific to neuronal membranes. The expression was found to be developmentally regulated.
By affinity chromatography, telencephalin was characterized as a 500 kDa glycoprotein consisting of four monomers. In subsequent studies, the target cDNA was generated and considerable homology to the intercellular adhesion molecule, ICAM, family found (Yoshihara et al. 1994). Telencephalin was included as the fifth and so far the youngest member of the family. Consistent with the nomenclature, it was renamed ICAM-5 (Gahmberg 1997).
Like all other members of the ICAM family, ICAM-5 belongs to the immunoglobulin, Ig, superfamily, and it is a type 1 integral protein. The extracellular part of the protein is the most complex in the ICAM-family with nine Ig domains. The Ig domains are classical folds of two antiparallel β sheets, linked by one or two disulphide bonds.
The extracellular part is heavily glycosylated with eight potential N-linked glycosylation sites. The N-glycosylation at asparagine-54 in the first Ig domain of the protein was shown to be essential for the dendrititic membrane-specific distribution of ICAM-5. The mutated ICAM-5 with an unglycosylatable amino acid at position 54 was functionally impaired (Ohgomori et al. 2012).
Another specific feature of ICAM-5 is the distribution of charge in the extracellular part. The crystal structure of the four first Ig domains revealed that the two first domains contain patches of positive charges, while the third to the fifth Ig domains are negatively charged. The extracellular domain has a bent conformation with two sharp angles on either side on Ig domain-3 (Recacha et al. 2014). Interestingly, the intracellular tail has a segment highly enriched in the amino acids alanine and glycine. Their function, if any, remains to be determined.
Function and Binding Partners
All ICAMs bind to the lymphocyte function-associated antigen 1, LFA-1 (CD11a/CD18, αL/β2). LFA-1 is a leukocyte-specific integrin. The integrins are heterodimeric adhesion proteins with a wide expression profile. They consist of one α subunit and one β subunit. There are 18 different α subunits and 8 β subunits. The integrins can promote signaling both inside-out and outside-in. In the brain, ICAM-5 could potentially interact with resident microglia and infiltrating lymphocytes, expressing LFA-1.
The first two Ig domains of ICAM-5 have been crystallized in complex with the I-domain of the α chain of LFA-1, and the glutamic acid-37 was found to be essential for this ligand-receptor interaction (Zhang et al. 2008).
Activation of N-methyl-d-aspartic acid, NMDA, receptors induces shedding of the extracellular portion of ICAM-5. This is mediated by matrix metalloproteases, mainly MMP-2 and -9 (Tian et al. 2007). MMPs are zinc-dependent proteases released in a pro-form. Once activated in the extracellular space, they can target several substrates. ICAM-5 is cut at two sites, generating two major fragments of approximately 85 kDa and 110 kDa. ICAM-5 dissociation from the actin cytoskeleton promotes the cleavage (Tian et al. 2008). The shedding also occurs during early long-term potentiation, LTP (Conant et al. 2010). The soluble ICAM-5 could promote spine and synaptic maturation by (1) binding to β1 integrins leading to subsequent phosphorylation of cofilin (Conant et al. 2011); (2) increasing GluA1 phosphorylation and trafficking to the plasma membrane, increasing the frequency of mini excitatory postsynaptic currents, mEPSC; and (3) inducing elongation of filopodia. Interestingly, ablation of ICAM-5 also increases the mEPSC frequency (Ning et al. 2013).
The psychostimulant methamphetamine can also induce MMP-mediated shedding of ICAM-5. Methamphetamine treatment caused an elevated level of MMP-9 in the hippocampus and striatum in vivo. In this case, the sICAM-5 was suggested to induce integrin β1-mediated phosphorylation of cofilin and subsequent spine maturation (Conant et al. 2011).
ICAM-5 causes a morphological change in microglia and T-cells and it may be important in their binding to telencephalic dendrites and somas. The immunological function of ICAM-5 is, however, different as compared to that of its sibling, ICAM-1. While the soluble form of ICAM-1 is proinflammatory, ICAM-5 was shown to be immunosuppressive. Soluble ICAM-5 downregulates the T-cell receptor-mediated signaling pathway and decreases the secretion of cytokines. Also, the activation markers CD25, CD40, and CD69 are downregulated (Tian et al. 2008).
In the initial contact between two synaptic elements, ICAM-5 on the dendritic terminal may bind the integrin very late antigen-5, VLA-5 (CD49e/CD29, α5/β1) on the axonal terminal. Here also the binding is mediated through the two first Ig domains of ICAM-5. This interaction reduces the cleavage of ICAM-5 and suggests a juvenilizing effect on the new synapse (Ning et al. 2013).
Role in Disease
Soluble ICAM-5 can be found in the cerebrospinal fluid and plasma of patients with various diseases. Hypoxic ischemia, acute encephalitis, and temporal-lobe epilepsy have been shown to induce the cleavage of ICAM-5. In epilepsy, studies show reduced amounts of sICAM-5 in patient sera. To date, the only known mechanism causing the cleavage of extracellular ICAM-5 is MMP-mediated proteolysis. Soluble ICAM-5 has been shown to modulate cytokine production. This was shown with T-cells in vitro, and a change in cytokine profile was also observed in Herpes simplex virus infection. The viral gene product UOL was found to bind ICAM-5 and the infection caused a decrease in ICAM-5 expression. A mutated virus lacking the UOL gene showed decreased neurovirulence and a lower level of cytokine production (Tse et al. 2009).
Presenilin-1 and -2 which are part of the gamma-secretase complex can associate with the transmembrane region of ICAM-5. This binding promoted an ARF6-mediated removal of ICAM-5 through an autophagic pathway (Raemaekers et al. 2012). Presenilin-1 is an important player in Alzheimer’s disease since the gamma secretase complex generates the cytotoxic form of the amyloid precursor protein, APP, β-amyloid. In the familial form of Alzheimer’s disease, the APP contains mutated amino acids at the site that binds presenilins. Interestingly, ICAM-5 interacts with the same region of presenilins (Annaert et al. 2001). Around the β-amyloid plaques, the expression of ICAM-5 is decreased. Further research in this field demonstrated a protective role for ICAM-5, dampening β-amyloid-induced apoptosis by activating the ERM-family/phosphatidylinositol-3-kinase/protein kinase B pathway (Yang et al. 2012).
Cell adhesion is critical in all stages of development and normal physiology. ICAM-5 is a complex and versatile adhesion molecule involved in signaling, regulating maturation of neuronal elements, and serving many other functions beyond adhesion. The expression of ICAM-5 is developmentally regulated and confined to the somatodendritic compartment of mammalian telencephalic neurons.
ICAM-5 can bind ligands on neurons and immune cells. Its cytoplasmic tail binds several actin cytoskeleton modifying proteins which can regulate synaptic maturation processes. Mice devoid of ICAM-5 have neurons with increased amounts of mature synapses and the mice perform slightly better in hippocampal mediated memory tasks, compared to the wild-type mice. However, the phenotype of ICAM-5 knockout mice is mild, and the mice live and reproduce normally.
Taken together, the studies done on ICAM-5 have potentially given interesting insights into higher brain functions mediated by the evolutionally youngest part of the mammalian brain. It seems to play a role in brain development, synaptic maturation, and immunological events. The gene is well conserved between species and still the knockout mice can hardly be told apart from wild-type. For future work it would be important to investigate the signaling capacity of ICAM-5, both intracellularly and extracellularly. These events could further elucidate how the molecule can contribute to synaptic plasticity.
- Yang H, Wu D, Zhang X, Wang X, Peng Y, Hu Z. Telencephalin protects PAJU cells from amyloid beta protein-induced apoptosis by activating the ezrin/radixin/moesin protein family/phosphatidylinositol-3-kinase/protein kinase B pathway. Neural Regen Res. 2012;7(28):2189–98.PubMedPubMedCentralGoogle Scholar