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

Abstract

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

“…Persistent overload of misfolded proteins causes a diverse array of disorders due to impaired functional protein synthesis and cell death [ 54 , 55 ], including neurodegenerative disease [ 30 ], dilated cardiomyopathy [ 56 ], and renal disease [ 57 ]. Another distinct mechanism by which ER stress causes human disease is that the UPR alters signaling pathways required for important cellular functions [ 38 ]. Obesity causes ER stress that induces the UPR, which may attenuate insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase and serine phosphorylation of insulin receptor substrate-1.…”

“…Some of them revealed neurodegenerative disorders at a very old age [ 35 , 36 ]. The recognition of the KDEL-retrieval sequence by the KDEL receptor also modulates the signal transduction related to the UPR via activation of some kinases like mitogen-activated protein kinases [ 37 , 38 ]. Although repeated morphine administration caused tolerance in wild-type mice, mutant BiP mice showed less tolerance.…”

Critical Impact of Different Conserved Endoplasmic Retention Motifs and Dopamine Receptor Interacting Proteins (DRIPs) on Intracellular Localization and Trafficking of the D2 Dopamine Receptor (D2-R) Isoforms

“…Retrieval of proteins mediated by the KDEL receptor can occur from different sites, ranging from early Golgi complex locations to trans Golgi networks [ 30 ]. In the GA, the KDEL receptor could associate with Gα o , one of the abundant Gα subunit and regulate receptor trafficking through G-proteins [ 59 ].…”

Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response

“…An excess of cytoplasmic Ca 2+ would then enter the mitochondria, thus resulting in the activation of caspases and ultimately, cell death [22,23]. Since ER molecular chaperones are Ca 2+ binding proteins, it follows that aberrant Ca 2+ mobilization will lead to the disruption of protein folding in the ER, thereby causing ER stress [24].…”

“…These proteins are subsequently translocated to the ER membrane and undergo folding to become functional proteins with mature structures; this process involves significant interaction with molecular chaperones in the ER, including binding immunoglobulin protein (BiP). Subsequently, these proteins are transported to the secretory pathway to carry out their functional role; for example, as such as cell surface receptors or secretory proteins [24,25]. ER stresses, such as hypoxia, ischemia, malnutrition, or mutation, initiates an adaptive response referred to as the unfolded protein response (UPR) [26].…”