The opioid peptide dynorphin mediates heterosynaptic depression of hippocampal mossy fibre synapses and modulates long-term potentiation

Abstract

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

The dynorphin/κ-opioid receptor system and its role in psychiatric disorders

“…DYN immunoreactivity in the hippocampus is densest in the mossy fiber pathway from the dentate gyrus to CA3 with little or no expression in other hippocampal regions [219,220]. KOR activation by endogenous or exogenous ligands decreases mossy fiber pathway synaptic transmission in guinea pigs, LongEvans rats, DBA/2 and C57BL/6 mice, and hamster [221][222][223][224], an effect that is absent in Sprague-Dawley rats [222]. This suggests the existence of strain differences in rats.…”

“…DYN inhibition of mossy fiber transmission is enhanced after tetanic stimulation of mossy fibers and this enhancement of inhibition is specific to tetanized, but not non-tetanized, mossy fiber pathway synapses in the same preparation [223]. Moreover, DYN peptides are recruited to produce heterosynaptic inhibition in the mossy fiber pathway [221,223]. Thus, DYNs released in response to strong stimuli may decrease function of mossy fiber pathway synapses that have low levels of activity, suggesting DYN/KOR modulation of synaptic transmission appears to be synapse-selective and highly dependent on activity.…”

“…Nor-BNI bath application promotes induction of LTP of the mossy fiber pathway when sub-threshold tetanic stimulation protocols are utilized [223]. DYN inhibition of mossy fiber transmission is enhanced after tetanic stimulation of mossy fibers and this enhancement of inhibition is specific to tetanized, but not non-tetanized, mossy fiber pathway synapses in the same preparation [223]. Moreover, DYN peptides are recruited to produce heterosynaptic inhibition in the mossy fiber pathway [221,223].…”

“…LTP has been suggested to be one type of synaptic plasticity that mediates learning and memory function [428]. As mentioned above, KOR activation decreases neurotransmission of both perforant path and mossy fiber pathways in the hippocampus [176,223,224]; providing a cellular basis for the detrimental effect of DYN and exogenous KOR agonists on hippocampal-dependent spatial memory.…”

mGluR2 acts through inhibitory Gα subunits to regulate transmission and long-term plasticity at hippocampal mossy fiber-CA3 synapses

“…One example is kappa receptors, which bind the opioid peptide dynorphin released by mossy fibers (32). Application of dynorphin causes suppression of synaptic activity and inhibition of LTP similar to that caused by group II mGluR agonists (33,34), raising the possibility that these receptors may regulate mossy fiber activity through inhibitory G␣ activity in a manner similar to that of mGluR2s. Furthermore, adenylate cyclase inhibition by inhibitory G␣ signaling may also play a role in another presynaptically expressed form of LTD at Schaffer collateral synapses that results from coordinated adenylate cyclase inhibition (supplied by either mGluR2 or adenosine A1 receptor agonists) and elevation of [cGMP] (35)(36)(37)(38).…”