The Role of BiP Retrieval by the KDEL Receptor in the Early Secretory Pathway and its Effect on Protein Quality Control and Neurodegeneration

Protein quality control in the early secretory pathway is a ubiquitous eukaryotic mechanism for adaptation to endoplasmic reticulum (ER) stress. An ER molecular chaperone, immunoglobulin heavy chain-binding protein (BiP), is one of the essential components in this process. BiP interacts with nascent proteins to facilitate their folding. BiP also plays an important role in preventing aggregation of misfolded proteins and regulating the ER stress response when cells suffer various injuries. BiP is a member of the 70-kDa heat shock protein (HSP70) family of molecular chaperones that resides in the ER. Interaction between BiP and unfolded proteins is mediated by a substrate-binding domain and a nucleotide-binding domain for ATPase activity, leading to protein folding and maturation. BiP also possesses a retrieval motif in its carboxyl terminal. When BiP is secreted from the ER, the Lys-Asp-Glu-Leu (KDEL) receptor in the post-ER compartments binds with the carboxyl terminal KDEL sequence of BiP and returns BiP to the ER via coat protein complex I (COPI) vesicular transport. Although yeast studies showed that BiP retrieval by the KDEL receptor is not essential in single cells, it is crucial for multicellular organisms, where some essential proteins require retrieval to facilitate folding and maturation. Experiments in knock-in mice expressing mutant BiP with the retrieval motif deleted revealed a unique role of BiP retrieval by the KDEL receptor in neuronal development and age-related neurodegeneration

Pathogenic Effects of Impaired Retrieval between the Endoplasmic Reticulum and Golgi Complex

Cellular activities, such as growth and secretion, are dependent on correct protein folding and intracellular protein transport. Injury, like ischemia, malnutrition, and invasion of toxic substances, affect the folding environment in the endoplasmic reticulum (ER). The ER senses this information, following which cells adapt their response to varied situations through the unfolded protein response. Activation of the KDEL receptor, resulting from the secretion from the ER of chaperones containing the KDEL sequence, plays an important role in this adaptation. The KDEL receptor was initially shown to be necessary for the retention of KDEL sequence-containing proteins in the ER. However, it has become clear that the activated KDEL receptor also regulates bidirectional transport between the ER and the Golgi complex, as well as from the Golgi to the secretory pathway. In addition, it has been suggested that the signal for KDEL receptor activation may also affect several other cellular activities. In this review, we discuss KDEL receptor-mediated bidirectional transport and signaling and describe disease models and human diseases related to KDEL receptor dysfunction

Pharmacological Chaperones Attenuate the Development of Opioid Tolerance

Opioids are potent analgesics widely used to control acute and chronic pain, but long-term use induces tolerance that reduces their effectiveness. Opioids such as morphine bind to mu opioid receptors (MORs), and several downstream signaling pathways are capable of inducing tolerance. We previously reported that signaling from the endoplasmic reticulum (ER) contributed to the development of morphine tolerance. Accumulation of misfolded proteins in the ER induced the unfolded protein response (UPR) that causes diverse pathological conditions. We examined the effects of pharmacological chaperones that alleviate ER stress on opioid tolerance development by assessing thermal nociception in mice. Pharmacological chaperones such as tauroursodeoxycholic acid and 4-phenylbutyrate suppressed the development of morphine tolerance and restored analgesia. Chaperones alone did not cause analgesia. Although morphine administration induced analgesia when glycogen synthase kinase 3β (GSK3β) was in an inactive state due to serine 9 phosphorylation, repeated morphine administration suppressed this phosphorylation event. Co-administration of chaperones maintained the inactive state of GSK3β. These results suggest that ER stress may facilitate morphine tolerance due to intracellular crosstalk between the UPR and MOR signaling. Pharmacological chaperones may be useful in the management of opioid misuse

A comparative study of the acute and long-term prognosis for mouse models undergoing laparoscopic surgery under continuous intra-abdominal perfusion with either CO2 gas or saline

Background: We developed a water-filled laparoendoscopic surgery (WaFLES) method using an isotonic irrigant like physiological saline instead of carbon dioxide (CO2) insufflation. Although surgical experimentation in porcine models has revealed some advantages, the effect of perfusate absorption remains uncertain. Here, we examined the acute and long-term prognosis of this method in mouse models. Materials and methods: CO2 gas or physiological saline was continuously perfused into mice for 1 h. Body-weight fluctuation was observed for 100 days in the two groups and control anesthesia group of mice. In addition, the induction of stress proteins and cytokines was evaluated immediately after perfusion. Results: Mice perfused with saline showed a temporary 30% increase in body weight during perfusion; however, this increase was not significant when assessed one day later. There was no significant increase in either IL6 or TNFα levels in the peritoneal lavage fluid obtained from any of the three groups. There were no significant changes in the expression of HSP70 or BiP. All mice survived over the long-term observation period of 100 days without any evidence of body-weight fluctuation (P = 0.7408, N = 5 for each group). Conclusion: WaFLES showed a good prognosis in a mouse model, thus indicating significant potential for clinical application