Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
J Cell Biol. 2012 Feb 20;196(4):529-43. doi: 10.1083/jcb.201109044. Epub 2012 Feb 13.
Neuropeptide signaling is integral to many aspects of neural communication, particularly modulation of membrane excitability and synaptic transmission. However, neuropeptides have not been clearly implicated in synaptic growth and development. Here, we demonstrate that cholecystokinin-like receptor (CCKLR) and drosulfakinin (DSK), its predicted ligand, are strong positive growth regulators of the Drosophila melanogaster larval neuromuscular junction (NMJ). Mutations of CCKLR or dsk produced severe NMJ undergrowth, whereas overexpression of CCKLR caused overgrowth. Presynaptic expression of CCKLR was necessary and sufficient for regulating NMJ growth. CCKLR and dsk mutants also reduced synaptic function in parallel with decreased NMJ size. Analysis of double mutants revealed that DSK/CCKLR regulation of NMJ growth occurs through the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element binding protein (CREB) pathway. Our results demonstrate a novel role for neuropeptide signaling in synaptic development. Moreover, because the cAMP-PKA-CREB pathway is required for structural synaptic plasticity in learning and memory, DSK/CCKLR signaling may also contribute to these mechanisms.
神经肽信号对于神经通讯的许多方面都至关重要，特别是对于调节细胞膜兴奋性和突触传递。然而，神经肽在突触的生长和发育中作用并不明确。在这里，我们证明胆囊收缩素样受体（CCKLR）及其预测配体，脑啡肽（DSK），是黑腹果蝇幼虫肌神经接点（NMJ）的强正向生长调控因子。CCKLR 或 dsk 的突变会导致 NMJ 严重生长不良，而 CCKLR 的过表达则会导致过度生长。CCKLR 的突触前表达对于调节 NMJ 生长是必要且充分的。CCKLR 和 dsk 突变体还与 NMJ 大小的减少平行地降低了突触功能。双突变体的分析表明，DSK/CCKLR 对 NMJ 生长的调控是通过环腺苷酸（cAMP）-蛋白激酶 A（PKA）-cAMP 反应元件结合蛋白（CREB）通路进行的。我们的结果表明神经肽信号在突触发育中具有新的作用。此外，由于 cAMP-PKA-CREB 通路对于学习和记忆中的结构型突触可塑性是必需的，DSK/CCKLR 信号也可能对这些机制有贡献。
