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

Rui ting Mao, Shi qi Guo, Guo Zhang, Ya dong Li, Ju ping Xu, Hui ying Wang, Ping Fu, Cui ping Liu, Shao qian Wu, Ping Chen, Yu shuo Mei, Qing chun Jin, Cheng yi Liu, Yan chu fei Zhang, Xue ying Ding, Wei jia Liu, Elena V. Romanova, Hai bo Zhou, Elizabeth C. Cropper, James W. CheccoJonathan V. Sweedler, Jian Jing

Research output: Contribution to journalArticlepeer-review

Abstract

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 desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

Original languageEnglish (US)
Article number107556
JournalJournal of Biological Chemistry
Volume300
Issue number8
DOIs
StatePublished - Aug 2024

Keywords

  • Aplysia
  • desensitization
  • G protein-coupled receptor (GPCR)
  • ligand–receptor interaction
  • neuropeptide
  • signal transduction
  • tachykinin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Two C-terminal isoforms of Aplysia tachykinin–related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms'. Together they form a unique fingerprint.

Cite this