Mizunami Makoto, Nemoto Yuko, Terao Kanta, Hamanaka Yoshitaka, Matsumoto Yukihisa
Faculty of Science, Hokkaido University, Sapporo, Japan.
Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
PLoS One. 2014 Sep 12;9(9):e107442. doi: 10.1371/journal.pone.0107442. eCollection 2014.
Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a key molecule in many systems of learning and memory in vertebrates, but roles of CaMKII in invertebrates have not been characterized in detail. We have suggested that serial activation of NO/cGMP signaling, cyclic nucleotide-gated channel, Ca(2+)/CaM and cAMP signaling participates in long-term memory (LTM) formation in olfactory conditioning in crickets, and here we show participation of CaMKII in LTM formation and propose its site of action in the biochemical cascades. Crickets subjected to 3-trial conditioning to associate an odor with reward exhibited memory that lasts for a few days, which is characterized as protein synthesis-dependent LTM. In contrast, animals subjected to 1-trial conditioning exhibited memory that lasts for only several hours (mid-term memory, MTM). Injection of a CaMKII inhibitor prior to 3-trial conditioning impaired 1-day memory retention but not 1-hour memory retention, suggesting that CaMKII participates in LTM formation but not in MTM formation. Animals injected with a cGMP analogue, calcium ionophore or cAMP analogue prior to 1-trial conditioning exhibited 1-day retention, and co-injection of a CaMKII inhibitor impaired induction of LTM by the cGMP analogue or that by the calcium ionophore but not that by the cAMP analogue, suggesting that CaMKII is downstream of cGMP production and Ca(2+) influx and upstream of cAMP production in biochemical cascades for LTM formation. Animals injected with an adenylyl cyclase (AC) activator prior to 1-trial conditioning exhibited 1-day retention. Interestingly, a CaMKII inhibitor impaired LTM induction by the AC activator, although AC is expected to be a downstream target of CaMKII. The results suggest that CaMKII interacts with AC to facilitate cAMP production for LTM formation. We propose that CaMKII serves as a key molecule for interplay between Ca(2+) signaling and cAMP signaling for LTM formation, a new role of CaMKII in learning and memory.
钙/钙调蛋白（CaM）依赖性蛋白激酶II（CaMKII）是脊椎动物许多学习和记忆系统中的关键分子，但CaMKII在无脊椎动物中的作用尚未得到详细表征。我们曾提出，NO/cGMP信号、环核苷酸门控通道、Ca(2+)/CaM和cAMP信号的系列激活参与蟋蟀嗅觉条件反射中的长期记忆（LTM）形成，在此我们展示了CaMKII参与LTM形成，并提出其在生化级联反应中的作用位点。接受3次将气味与奖励相关联的条件反射的蟋蟀表现出持续数天的记忆，这被表征为蛋白质合成依赖性LTM。相比之下，接受1次条件反射的动物表现出仅持续数小时的记忆（中期记忆，MTM）。在3次条件反射前注射CaMKII抑制剂会损害1天的记忆保持，但不会损害1小时的记忆保持，这表明CaMKII参与LTM形成但不参与MTM形成。在1次条件反射前注射cGMP类似物、钙离子载体或cAMP类似物的动物表现出1天的记忆保持，同时注射CaMKII抑制剂会损害cGMP类似物或钙离子载体诱导的LTM，但不会损害cAMP类似物诱导的LTM，这表明在LTM形成的生化级联反应中，CaMKII在cGMP产生和Ca(2+)内流的下游以及cAMP产生的上游。在1次条件反射前注射腺苷酸环化酶（AC）激活剂的动物表现出1天的记忆保持。有趣的是，尽管AC预计是CaMKII的下游靶点，但CaMKII抑制剂会损害AC激活剂诱导的LTM。结果表明，CaMKII与AC相互作用以促进cAMP产生从而形成LTM。我们提出，CaMKII作为Ca(2+)信号和cAMP信号相互作用以形成LTM的关键分子，这是CaMKII在学习和记忆中的新作用。
