Proteases involved in long-term potentiation

Abstract

Much attention has been paid to proteases involved in long-term potentiation (LTP). Calpains, Ca-dependent cysteine proteases, have first been demonstrated to be the mediator of LTP by the proteolytic cleavage of fodrin, which allows glutamate receptors located deep in the postsynaptic membrane to move to the surface. It is now generally considered that calpain activation is necessary for LTP formation in the cleavage of substrates such as protein kinase Cζ, NMDA receptors, and the glutamate receptor-interacting protein. Recent studies have shown that serine proteases such as tissue-type plasminogen activator (tPA), thrombin, and neuropsin are involved in LTP. tPA contributes to LTP by both receptor-mediated activation of cAMP-dependent protein kinase and the cleavage of NMDA receptors. Thrombin induces a proteolytic activation of PAR-1, resulting in activation of protein kinase C, which reduces the voltage-dependent Mg²⁺ blockade of NMDA receptor-channels. On the other hand, neuropsin may act as a regulatory molecule in LTP via its proteolytic degradation of extracellular matrix protein such as fibronectin. In addition to such neuronal proteases, proteases secreted from microglia such as tPA may also contribute to LTP. The enzymatic activity of each protease is strictly regulated by endogenous inhibitors and other factors in the brain. Once activated, proteases can irreversibly cleave peptide bonds. After cleavage, some substrates are inactivated and others are activated to gain new functions. Therefore, the issue to identify substrates for each protease is very important to understand the molecular basis of LTP.

Introduction

Long-term potentiation (LTP), a long lasting activity-dependent increase in the size of a synaptic response, was first described by Bliss and Lømo (1973) [3] and has since been considered as a cellular mechanism underlying learning and memory in the brain. Glutamate activation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor subtypes are essential events in LTP. LTP has two distinct phases: early-phase LTP (E-LTP) and late-phase LTP (L-LTP) that requires new protein synthesis and activation of cAMP-dependent protein kinase (PKA).

There is growing evidence that proteolytic cascades are closely associated with both E-LTP and L-LTP. To better understand the precise roles of each protease in LTP, it is the fundamental issue to elucidate their substrates. We will summarize recent studies on the proteolytic systems that play important roles in LTP.