Capacity to Prolong Changes and Induce Permanent Functional Alterations

While phosphorylation and dephosphorylation events are, in many cases, quite transient, the activity of most kinases and some phosphatases can be prolonged via several means including, in particular, autophosphorylation, through which an activated kinase phosphorylates itself as well as other substrates. Autophosphorylated kinases continue to phosphorylate substrates following degradation of the message responsible for their activation. Provided phosphatase activity is constrained, therefore, they could maintain information while structural modifications, proposed by many to be necessary to produce permanent memory, occur. The idea that kinase autophosphorylation may act to store information has been comprehensively explored by Lisman, who argued in 1985 that a bistable autophosphorylating kinase could store information indefinitely.104

According to Lisman's initial model, a switching mechanism could be formed from a kinase capable of autophosphorylation and a phosphatase able to dephosphorylate the kinase. In an initial state the kinase is dephosphorylated and incoming information triggers autophosphorylation. If only a small proportion of the available kinase molecules are activated, they are rapidly dephosphorylated, causing loss of the 'biologically unimportant' information. If the stimulus is sufficiently strong to activate many molecules, however, the limited amount of phosphatase available cannot counteract the autophosphorylation. All kinase molecules are eventually activated and the activity is maintained indefinitely. It results, therefore, in permanent phosphorylation of critical substrates and a stable record of the information.

This model represents only one way in which phosphorylation and dephosphorylation could contribute to prolonged information storage. Another popular, not necessarily mutually exclusive, model holds that permanent memory formation depends on changes in gene expression and protein synthesis. Any change to gene expression or protein synthesis is likely to depend heavily on phosphorylation since both transcription and translation are regulated at many points by changes in the phosphorylation state of critical substrate proteins.2 2

Figure 2. A) Signal amplification-a cAMP signal stimulates PKA, resulting in increased phosphorylation of PKA substrates including INH-1 and DARPP-32. This leads to inhibition of PP1, decreasing dephos-phorylation ofPKA substrates so that the response to PKA is amplified. B) Signal synergism-phosphorylation of INH-1 in response to activation of PKA results in inhibition of PP1. If Ca2+-dependent systems are also active, this synergistically increases phosphorylation of substrates for these systems. C) Signal antagonism-dephosphorylation of INH-1 by PP2B means that extracellular signals that act through Ca2+-driven systems can antagonise the actions of PKA.

Figure 2. A) Signal amplification-a cAMP signal stimulates PKA, resulting in increased phosphorylation of PKA substrates including INH-1 and DARPP-32. This leads to inhibition of PP1, decreasing dephos-phorylation ofPKA substrates so that the response to PKA is amplified. B) Signal synergism-phosphorylation of INH-1 in response to activation of PKA results in inhibition of PP1. If Ca2+-dependent systems are also active, this synergistically increases phosphorylation of substrates for these systems. C) Signal antagonism-dephosphorylation of INH-1 by PP2B means that extracellular signals that act through Ca2+-driven systems can antagonise the actions of PKA.

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