Knocking Out Sigma-1 Receptors Reveals Diverse Health Problems.

Sigma-1 receptor (Sig-1R) is a protein present in several organs such as brain, lung, and heart. In a cell, Sig-1R is mainly located across the membranes of the endoplasmic reticulum and more specifically at the mitochondria-associated membranes. Despite numerous studies showing that Sig-1R could be targeted to rescue several cellular mechanisms in different pathological conditions, less is known about its fundamental relevance. In this review, we report results from various studies and focus on the importance of Sig-1R in physiological conditions by comparing Sig-1R KO mice to wild-type mice in order to investigate the fundamental functions of Sig-1R. We note that the Sig-1R deletion induces cognitive, psychiatric, and motor dysfunctions, but also alters metabolism of heart. Finally, taken together, observations from different experiments demonstrate that those dysfunctions are correlated to poor regulation of ER and mitochondria metabolism altered by stress, which could occur with aging.

Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain.

Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER) chaperones implicated in neuropathic pain. Here we examine if the Sig-1R may relate to neuropathic pain at the level of dorsal root ganglia (DRG). We focus on the neuronal excitability of DRG in a "spare nerve injury" (SNI) model of neuropathic pain in rats and find that Sig-1Rs likely contribute to the genesis of DRG neuronal excitability by decreasing the protein level of voltage-gated Cav2.2 as a translational inhibitor of mRNA. Specifically, during SNI, Sig-1Rs translocate from ER to the nuclear envelope via a trafficking protein Sec61ß. At the nucleus, the Sig-1R interacts with cFos and binds to the promoter of 4E-BP1, leading to an upregulation of 4E-BP1 that binds and prevents eIF4E from initiating the mRNA translation for Cav2.2. Interestingly, in Sig-1R knockout HEK cells, Cav2.2 is upregulated. In accordance with those findings, we find that intra-DRG injection of Sig-1R agonist (+)pentazocine increases frequency of action potentials via regulation of voltage-gated Ca2+ channels. Conversely, intra-DRG injection of Sig-1R antagonist BD1047 attenuates neuropathic pain. Hence, we discover that the Sig-1R chaperone causes neuropathic pain indirectly as a translational inhibitor.

Cocaine-induced endocannabinoid signaling mediated by sigma-1 receptors and extracellular vesicle secretion.

Cocaine is an addictive drug that acts in brain reward areas. Recent evidence suggests that cocaine stimulates synthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in midbrain, increasing dopamine neuron activity via disinhibition. Although a mechanism for cocaine-stimulated 2-AG synthesis is known, our understanding of 2-AG release is limited. In NG108 cells and mouse midbrain tissue, we find that 2-AG is localized in non-synaptic extracellular vesicles (EVs) that are secreted in the presence of cocaine via interaction with the chaperone protein sigma-1 receptor (Sig-1R). The release of EVs occurs when cocaine causes dissociation of the Sig-1R from ADP-ribosylation factor (ARF6), a G-protein regulating EV trafficking, leading to activation of myosin light chain kinase (MLCK). Blockade of Sig-1R function, or inhibition of ARF6 or MLCK also prevented cocaine-induced EV release and cocaine-stimulated 2-AG-modulation of inhibitory synapses in DA neurons. Our results implicate the Sig-1R-ARF6 complex in control of EV release and demonstrate that cocaine-mediated 2-AG release can occur via EVs.

Ellagitannins of Davidia involucrata. I. Structure of Davicratinic Acid A and Effects of Davidia Tannins on Drug-Resistant Bacteria and Human Oral Squamous Cell Carcinomas.

We isolated a new ellagitannin, davicratinic acid A (5), together with four known ellagitannins, davidiin (1), granatin A (2), pedunculagin (3), and 3-O-galloylgranatin A (4), from an aqueous acetone extract of dried Davidia involucrata leaves. The known ellagitannins were identified based on spectroscopic data. The structure of davicratinic acid A (5), a monomeric ellagitannin possessing a unique, skew-boat glucopyranose core, was established based on spectroscopic data. Additionally, we examined the effects of several tannins with good yields from this plant on drug-resistant bacteria and human oral squamous cell carcinomas, and found that davidiin (1) exhibited the most potent antibacterial and antitumor properties among the tannins examined.

A flowering integrator, SOC1, affects stomatal opening in Arabidopsis thaliana.

Stomatal movements are regulated by multiple environmental signals. Recent investigations indicate that photoperiodic flowering components, such as CRY, GI, CO, FT and TSF, are expressed in guard cells and positively affect stomatal opening in Arabidopsis thaliana. Here we show that SOC1, which encodes a MADS box transcription factor and integrates multiple flowering signals, also exerts a positive effect on stomatal opening. FLC encodes a potent repressor of FT and SOC1, and FRI acts as an activator of FLC. Thus, we examined stomatal phenotypes in FRI-Col, which contains an active FRI allele of accession Sf-2 by introgression. We found higher expression of FLC and lower expression of FT, SOC1 and TSF in guard cells from FRI-Col than in those from Col. Light-induced stomatal opening was significantly suppressed in FRI-Col. Interestingly, vernalization of FRI-Col partially restored light-induced stomatal opening, concomitant with a decrease of FLC and increase of FT, SOC1 and TSF. Furthermore, we observed the constitutive open-stomata phenotype in transgenic plants overexpressing SOC1-GFP (green fluorescent protein) in guard cells (SOC1-GFP overexpressor), and found that light-induced stomatal opening was significantly suppressed in a soc1 knockout mutant. RNA sequencing using epidermis from the SOC1-GFP overexpressor revealed that the expression levels of several genes involved in stomatal opening, such as BLUS1 and the plasma membrane H(+)-ATPases, were higher than those in background plants. From these results, we conclude that SOC1 is involved in the regulation of stomatal opening via transcriptional regulation in guard cells.

Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling.

Sigma-1 receptor (Sig-1R) is an integral membrane protein predominantly expressed in the endoplasmic reticulum. Sig-1R demonstrates a high affinity to various synthetic compounds including well-known psychotherapeutic drugs in the central nervous system (CNS). For that, it is considered as an alternative target for psychotherapeutic drugs. On the cellular level, when Sig-1R is activated, it is known to play a role in neuroprotection and neurite elongation. These effects are suggested to be mediated by its ligand-operated molecular chaperone activity, and/or upregulation of various Ca(2+) signaling. In addition, recent studies show that Sig-1R activation induces neurite outgrowth via neurotrophin signaling. Here, we tested the hypothesis that Sig-1R activation promotes neurite elongation through activation of tropomyosin receptor kinase (Trk), a family of neurotrophin receptors. We found that 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084), a selective Sig-1R agonist, significantly promoted neurite outgrowth, and K252a, a Trk inhibitor, attenuated Sig-1R-mediated neurite elongation in cerebellar granule neurons (CGNs). Moreover, we revealed that Sig-1R interacts with TrkB, and PRE-084 treatment enhances phosphorylation of Y515, but not Y706. Thus, our results indicate that Sig-1R activation promotes neurite outgrowth in CGNs through Y515 phosphorylation of TrkB.

[Predisposition to latex allergy undetected on preoperative evaluation: a case report].

A 70-year-old man was scheduled to undergo laparoscopic total gastrectomy for stomach cancer. He had no history of atopy, fruit allergies, or frequent exposure to natural rubber. Preoperative latex-specific IgE antibodies were negative. Anesthesia was induced, and the surgery was started uneventfully. Soon after the surgeon had begun to manipulate the intestine, the blood pressure suddenly dropped to 27/21 mmHg. Facial flushing was also observed. Anaphylactic shock caused by latex was strongly suspected, and surgery was immediately halted. The surgical gloves were changed to latex-free ones, and adrenaline was administered. The blood pressure was gradually normalized within 30 min, and the facial flushing mostly disappeared. Postoperative laboratory examination revealed that serum tryptase had increased to 34.4 microg l-1, 40 minutes after the onset of anaphylaxis, and decreased to 19.4 microg l-1, 24 hours than later. Latex-specific IgE antibodies and a prick test with latex were both positive. Consequently, the diagnosis of latex-induced anaphylactic reaction was confirmed. Because even detailed questioning and examination does not always identify such a predisposition, avoiding contactwith latex products is more rational exhaustively checking every preoperative patient for latex allergy

[Anesthetic management for laparoscopic adrenalectomy in a pregnant patient with Cushing's syndrome].

Cushing's syndrome is extremely rare during pregnancy, because it often causes amenorrhea and infertility. We experienced a case of Cushing's syndrome in the 23rd week of pregnancy receiving laparoscopic surgery. It was difficult to control the blood pressure and heart rate, but we succeeded in the safe management of both mother and fetus.

[Esophageal injury after insertion of a transesophageal echocardiography probe in a patient with an aberrant right subclavian artery].

We describe a case of an esophageal injury caused by insertion of a transesophageal cardiac echo probe in a 66-year-old man with an aberrant right subclavian artery, who was scheduled for Bentall surgery for aortic regurgitation and annuloaortic ectasia. Preoperative CT scan showed an aberrant right subclavian artery compressed from the back of the esophagus. General anesthesia was induced with midazolam and fentanyl, and maintained with midazolam, remifentanil and fentanyl. After induction of anesthesia, a transesophageal cardiac echo probe was inserted without abnormal resistance. The operation was performed uneventfully. On the second day after surgery, gastrointestinal bleeding was suspected and the upper gastrointestinal endoscopy (GIF) was performed. GIF revealed ulceration at the mid-esophagus and gastroesophageal junction, and a large amount of fresh blood in the stomach. The location of the ulcer at mid-esophagus was likely to be over the aberrant right subclavian artery. Ulcers were treated conservatively. GIF on the postoperative day 16 revealed that ulcers had healed. Transesophageal echo probe insertion is potentially hazardous in a patient with an aberrant right subclavian artery. Although aberrant right subclavian artery is rare, transesophageal echocardiography should be performed with extreme caution.

[Suspected diltiazem intoxication resulting in repeated asystole after the induction of anesthesia].

We present a case of diltiazem intoxication resulting in repeated asystole after the induction of anesthesia. A 39-year-old man was diagnosed as subarachnoid hemorrhage, and cerebral aneurysm clipping was scheduled on the next day. Electrocardiogram revealed normal sinus rhythm with complete right bundle branch block. Continuous intravenous administration of diltiazem, nicardipine and midazolam were started for intractable hypertension and tachycardia. In the operating room, electrocardiogram showed atrioventricular nodal rhythm. Nicardipine and midazolam were stopped and anesthesia was induced with thiamylal, fentanyl and vecuronium, and was maintained with sevoflurane. After tracheal intubation, the patient developed asystole, and cardiopulmonary resuscitation was provided immediately. Diltiazem was stopped. Cardiac rhythm was restored 8 min afterwards; however, asystole recurred six times. Temporary cardiac pacing was effective, and percutaneous cardiopulmonary support (PCPS), intraaortic balloon pumping (IABP), and continuous hemodiafiltration (CHDF) were initiated. The operation was canceled. On the next day, normal sinus rhythm was restored and the temporary pacing, PCPS, IABP, and CHDF were discontinued. Cerebral aneurysm was treated by endovascular coiling and the patient was discharged from the hospital without sequelae. This case illustrates asystole associated with diltiazem intoxication. It is necessary to consider this potential complication when diltiazem is used.