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Integrins: the missing link

Audrey C. Brumback*, Robert Zorec*† and William J. Betz*

In 1952, Fatt & Katz demonstrated that bathing the frog neuromuscular junction in a hypertonic solution causes a calcium-independent increase in the frequency of miniature end plate potentials (mEPPs). Only recently has the molecular explanation for this phenomenon begun to take shape. The report by Kashani et al. in this issue of The Journal of Physiology represents an important advance in this direction that results from the merger of research on integrins and the effects of stretch and hypertonicity.

Integrins are heterodimeric transmembrane proteins that allow bidirectional signalling across the plasma membrane. Each combination of and subunits has unique ligands, signalling properties and localization. For instance, Cohen et al. (2000) demonstrated that active zones on motor nerve terminals contain the 31 integrin, which binds such extracellular matrix components as fibronectin, laminin and collagen.

Many integrins bind to a characteristic tripeptide sequence, arginine-glycine-aspartate (RGD), within their ligands. Therefore, one can assay for the involvement of integrins by competitively inhibiting the binding of their extracellular ligands with the addition of this peptides containing this motif. Chen & Grinnell (1997) used this method to show that the increase in mEPP frequency with muscle stretch is inhibited by bathing the preparation in RGD peptide.

In addition, in the past decade several advances have linked integrins to neurobiology, specifically the field of learning and memory. For example, Grotewiel et al. (1998) described the Drosophila memory mutant Volado that does not express a particular integrin subunit in the area of the brain devoted to olfactory learning in insects (the mushroom body). This integrin mutant shows decreased olfactory memories within 3 min of training, implying that integrins are important for short-term memory retention. Another set of experiments by Xiao et al. (1991) has demonstrated that blocking integrin binding to the extracellular matrix with the RGD peptide prevents the maintenance of long-term potentiation in central synapses. Together, these studies underscore the importance of integrins in neurobiology.

The report by Kashani et al. in this issue of The Journal of Physiology provides an important link between the studies on hypertonicity, stretch, and integrins. They demonstrate first that stretching the muscle increases the frequency of mEPPs in a calcium-independent manner. They then show a similar calcium-independent increase in mEPP frequency with the application of hypertonic solution. Finally, they show that the two effects overlap and that both are dependent on integrin binding. It is important to note that the effects of hypertonicity and stretch seen in these experiments occur very quickly and therefore probably do not depend on slow second messenger pathways. This suggests a model where integrins link tension changes to neurotransmitter release by physically interacting with molecules that normally mediate fusion of synaptic vesicles with the presynaptic plasma membrane. Of further interest in this regard is the recent study by Stevens & Williams (2000), who showed that, with increasing hypertonicity, FM dye release and uptake lags behind quantal transmitter release measured electrophysiologically in cultured hippocampal neurons, suggesting that hypertonicity promotes 'kiss and run' exocytosis.

Several testable questions emerge from these interesting studies. First, do the effects depend upon a physical link between pre- and postsynaptic cells? By destroying the frog cutaneous pectoris muscle in vivo and irradiating the area to kill progenitor satellite cells, Dunaevsky & Connor (1995) demonstrated a method to study the frog neuromuscular junction sans muscle. Since the basement membrane remains intact, this preparation provides a way to distinguish connections involved between the nerve terminal and muscle fibre versus those between nerve and basal lamina. In addition, one could determine if presynaptic connections to the basal lamina are necessary for the effects of hypertonicity by enzymatically digesting the basement membrane (Betz & Sakmann, 1971). Finally, in light of the recent evidence for hypertonicity-induced 'kiss and run' exocytosis (Stevens & Williams, 2000), the results presented by Kashani et al. make one wonder if the switch to 'kiss and run' exocytosis could also be integrin mediated. Blocking the effect with the addition of the RGD peptide or the newly discovered RGD-containing equinatoxin V (Pungercar et al. 1997) would provide good evidence for this.

In summary, the report by Kashani et al. links together a number of experiments, both past and future, and helps shed light on topics as seemingly diverse as memory and muscle stretch.

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