Two C-terminal isoforms of Aplysia tachykinin–related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms

作者：Rui-Ting Mao, Shi‐Qi Guo, Guo Zhang, Yadong Li, Juping Xu, Huiying Wang, Ping Fu, Cuiping Liu, Shao-Qian Wu, Ping Chen, Yu-Shuo Mei, Qing-Chun Jin, Cheng-Yi Liu, Yan-Chu-Fei Zhang, Xueying Ding, Weijia Liu, Elena V. Romanova, Haibo Zhou, Elizabeth C. Cropper, James W. Checco, Jonathan V. Sweedler, Jian Jing · 发表于：Journal of Biological Chemistry · 年份：2024 · DOI：10.1016/j.jbc.2024.107556 · 被引用次数：7 · 研究领域：Neurobiology and Insect Physiology Research、Neuropeptides and Animal Physiology、Receptor Mechanisms and Signaling

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent de...