Repetitive activation of hippocampal mossy fibers evokes a long-term potentiation (LTP) of synaptic responses in pyramidal cells in the CA3 region that is independent of N-methyl-D-aspartate receptor activation. Previous results suggest that the site for both the induction and expression of this form of LTP is presynaptic. Experimental elevation of cyclic adenosine 3',5'-monophosphate (cAMP) both mimics and interferes with tetanus-induced mossy fiber LTP, and blockers of the cAMP cascade block mossy fiber LTP. It is proposed that calcium entry into the presynaptic terminal may activate Ca(2+)-calmodulin-sensitive adenylyl cyclase I which, through protein kinase A, causes a persistent enhancement of evoked glutamate release.

In invertebrate nervous systems, some long-lasting increases in synaptic efficacy result from changes in the presynaptic cell. In the vertebrate nervous system, the best understood long-lasting change in synaptic strength is long-term potentiation (LTP) in the CA1 region of the hippocampus. Here the process is initiated postsynaptically, but the site of the persistent change is unresolved. Single CA3 hippocampal pyramidal cells receive excitatory inputs from associational-commissural fibers and from the mossy fibers of dentate granule cells and both pathways exhibit LTP. Although the induction of associational-commissural LTP requires in the postsynaptic cell N-methyl-D-aspartate (NMDA) receptor activation, membrane depolarization, and a rise in calcium, mossy fiber LTP does not. Paired-pulse facilitation, which is an index of increased transmitter release, is unaltered during associational-commissural LTP but is reduced during mossy fiber LTP. Thus, both the induction and the persistent change may be presynaptic in mossy fiber LTP but not in associational-commissural LTP.

The mossy fibre pathway in the hippocampus uses glutamate as a neurotransmitter, but also contains the opioid peptide dynorphin. Synaptic release of dynorphin causes a presynaptic inhibition of neighbouring mossy fibres and inhibits the induction and expression of mossy fibre long-term potentiation. These findings demonstrate a physiological role for a neuropeptide in the central nervous system, provide a functional basis for the coexistence of a neuropeptide with classic neurotransmitters and demonstrate the very different roles played by these two classes of signalling molecules.

LETTERS TO NATUREformation in both proN* and proN' (Table I). This suggests that PDI is primarily responsible for the rapid rate of BPTI folding in vivo.The conclusion that PDI principally accelerates the folding of kinetically trapped intermediates, such as N' and N*, provides an explanation for why the effects of PDI on the folding of BPTI are much greater than on RNase A. The folding of reduced RNase A is relatively rapid even in the absence of PDI 16 and therefore does not appear to be retarded substantially by the accumulation of structured intermediates. By contrast, formation of the native state of BPTI is hindered by the accumulation of highly structured intermediates. Thus, although the uncatalysed rate for folding of BPTI is substantially lower than for RNase A, the PDI-catalysed rates for folding are similar in the two proteins (see Table I legend).PDI could help formation of the final disulphide bond in the kinetically trapped intermediates, N' and N*, either by accelerating the intramolecular rearrangement of these intermediates (to N~~) or by catalysing the direct oxidation of a third native disulphide bond. In the case of N', we find that the other native two-disulphide species (N~~ and N*) accumulate rapidly in the presence of PDI (Fig. 3b). Moreover, PDI catalyses the rearrangement of N' (to N~~ and N*) in the absence of redox reagents (Fig. 3c). These observations demonstrate that PDI acts largely by increasing the rate of intramolecular rearrangement steps, although it is possible that PDI also accelerates direct oxidation (see also ref. 13).The mechanism by which PDI catalyses disulphide bond rearrangements in structured intermediates is not known. It is known, however, that addition of high concentrations of denaturant (6 M urea) accelerates the rate of rearrangement of the N' (ref. 9) and N* (ref. 8) intermediates, suggesting that the rearrangement of these species requires substantial loss of structure 10 . In addition, PDI has been observed to promote the reductive unfolding of structured intermediates of BPTI 13 and retinol-binding protein 17 . Finally, PDI is able to interact with a wide variety of unstructured peptides 1 s' 19 , in a manner similar to the Hsp70 family of molecular chaperones 20 . These considerations raise the interesting possibility that PDI functions in part by promoting both local unfolding and disulphide bond rearrangements in structured intermediates. D

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