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The aim of this study was to investigate experimentally if 5-HT3 single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT3-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding HTR3A (rs1062613) and HTR3B (rs1176744). First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn.

The serious coronavirus disease‐2019 (COVID‐19) was first reported in December 2019 in Wuhan, China. COVID‐19 is an infectious disease caused by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Angiotensin converting enzyme 2(ACE2) is the cellular receptor for SARS‐CoV‐2. Considering the critical roles of testicular cells for the transmission of genetic information between generations, we analyzed single‐cell RNA‐sequencing (scRNA‐seq) data of adult human testis. The mRNA expression of ACE2 was expressed in both germ cells and somatic cells. Moreover, the positive rate of ACE2 in testes of infertile men was higher than normal, which indicates that SARS‐CoV‐2 may cause reproductive disorders through pathway activated by ACE2 and the men with reproductive disorder may easily to be infected by SARS‐CoV‐2. The expression level of ACE2 was related to the age, and the mid‐aged with higher positive rate than young men testicular cells. Taken together, this research provides a biological background of the potential route for infection of SARS‐CoV‐2 and may enable rapid deciphering male‐related reproductive disorders induced by COVID‐19.

Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis. The neurotransmitter serotonin has both central and peripheral effects. Here, the authors show that adipocyte-derived serotonin regulates organismal energy homeostasis in mice by acting on adipocyte serotonin receptors on fat cells, which regulates lipolysis and thermogenesis in white and brown fat tissue.

Monoamine serotonin is a major neurotransmitter that acts on a wide range of central nervous system and peripheral nervous system functions and is known to have a role in various processes. Recently, it has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways. The natural flavonoid kaempferol (KAE) extracted from Cudrania tricuspidata is a secondary metabolite of the plant. Recently studies have confirmed that KAE possesses a neuroprotective effect because of its strong antioxidant activity. It has been confirmed that KAE is involved in the serotonergic pathway through an in vivo test. However, these results need to be confirmed at the molecular level, because the exact mechanism that is involved in such effects of KAE has not yet been elucidated. Therefore, the objective of this study is to confirm the interaction of KAE with 5-HT3A through electrophysiological studies at the molecular level using KAE extracted from Cudrania tricuspidata. This study confirmed the interaction between 5-HT3A and KAE at the molecular level. KAE inhibited 5-HT3A receptors in a concentration-dependent and voltage-independent manner. Site-directed mutagenesis and molecular-docking studies confirmed that the binding sites D177 and F199 are the major binding sites of human 5-HT3A receptors of KAE.

In preparation for the metabolic demands of pregnancy, β cells in the maternal pancreatic islets increase both in number and in glucose-stimulated insulin secretion (GSIS) per cell. Mechanisms have been proposed for the increased β cell mass, but not for the increased GSIS. Because serotonin production increases dramatically during pregnancy, we tested whether flux through the ionotropic 5-HT3 receptor (Htr3) affects GSIS during pregnancy. Pregnant Htr3a ⁻/⁻ mice exhibited impaired glucose tolerance despite normally increased β cell mass, and their islets lacked the increase in GSIS seen in islets from pregnant wild-type mice. Electrophysiological studies showed that activation of Htr3 decreased the resting membrane potential in β cells, which increased Ca ²⁺ uptake and insulin exocytosis in response to glucose. Thus, our data indicate that serotonin, acting in a paracrine/autocrine manner through Htr3, lowers the β cell threshold for glucose and plays an essential role in the increased GSIS of pregnancy.

The authors find that long-range axons from primary motor cortex (vM1) preferentially recruit vasointestinal peptide (VIP)-expressing interneurons in somatosensory cortex (S1). VIP neurons in turn inhibit somatostatin-expressing interneurons that target the distal dendrites of pyramidal cells in S1. This dis-inhibitory circuit is active during voluntary movement, suggesting that it participates in the modulation of primary cortical sensory processing by motor cortex. The influence of motor activity on sensory processing is crucial for perception and motor execution. However, the underlying circuits are not known. To unravel the circuit by which activity in the primary vibrissal motor cortex (vM1) modulates sensory processing in the primary somatosensory barrel cortex (S1), we used optogenetics to examine the long-range inputs from vM1 to the various neuronal elements in S1. We found that S1-projecting vM1 pyramidal neurons strongly recruited vasointestinal peptide (VIP)-expressing GABAergic interneurons, a subset of serotonin receptor–expressing interneurons. These VIP interneurons preferentially inhibited somatostatin-expressing interneurons, neurons that target the distal dendrites of pyramidal cells. Consistent with this vM1-mediated disinhibitory circuit, the activity of VIP interneurons in vivo increased and that of somatostatin interneurons decreased during whisking. These changes in firing rates during whisking depended on vM1 activity. Our results suggest previously unknown circuitry by which inputs from motor cortex influence sensory processing in sensory cortex.

Alpha7 nicotinic receptors (α7-nAChRs) are implicated in many neurological disorders, but how they fold and assemble is not well understood. Unlike native α7-nAChRs, α7-5HT3 chimeras fold efficiently in HEK cells and do not require chaperones RIC3 or TMEM35A (NACHO) for proper assembly. We investigated the effects of swapping 5HT3 and α7-receptor protein sequences on α7-5HT3R chimera surface expression in mammalian HEK293 or Bosc23 cells, or chimeric receptor function using Xenopus laevis oocytes with or without chaperones. α7-5HT3Rs, consisting of human α7-nAChRs with mouse 5HT3 transmembrane domains (TMs) express without chaperones as measured by cell surface alpha-bungarotoxin binding. However, when subunit TMs from α7-nAChRs and 5HT3Rs were mixed, chaperones were required. Substituting the SAP motif prior to the α7-nAChR “Latch” tail sequence for the 5HT3 C-terminal decreased expression relative to α7-nAChRs with chaperones. Chaperone effects on L264 and G265 mutations in M2 were also investigated. Some constructs that express well in HEK293 or Bosc23 cells are nonfunctional in oocytes with or without NACHO. Our data do not support direct binding of RIC3 or NACHO to the α7-nAChR TM4 (M4) region; instead, they emphasize the functional importance of the conserved SAP motif.

Targeting ligand-responsive receptors to specific groups of cells, a strategy known as chemogenetics, is a powerful tool in many neurological applications. There is increasing interest in extending these tools for human treatment. Magnus et al. designed chemogenetic ion channels that improve currently available systems and are activated by the clinically used antismoking drug varenicline. They engineered a ligand-binding domain less responsive to endogenous signals and identified agonists that function at nanomolar concentrations. The combination of drug and introduced channels transiently silenced neurons, with slow but effective washout, and induced behavioral changes in animal models after brain administration. Science , this issue p. eaav5282 Engineered receptors and potent agonists enable selective control of cells in vivo for research and potential therapies. Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel–based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

Neuronal α7 nicotinic receptors elicit rapid cation influx in response to acetylcholine (ACh) or its hydrolysis product choline. They contribute to cognition, synaptic plasticity, and neuroprotection and have been implicated in neurodegenerative and neuropsychiatric disorders. α7, however, often localizes distal to sites of nerve-released ACh and binds ACh with low affinity, and thus elicits its biological response with low agonist occupancy. To assess the function of α7 when ACh occupies fewer than five of its identical binding sites, we measured the open-channel lifetime of individual receptors in which four of the five ACh binding sites were disabled. To improve the time resolution of the inherently brief α7 channel openings, background mutations or a potentiator was used to increase open duration. We find that, in receptors with only one intact binding site, the open-channel lifetime is indistinguishable from receptors with five intact binding sites, counter to expectations from prototypical neurotransmitter-gated ion channels where the open-channel lifetime increases with the number of binding sites occupied by agonist. Replacing the membrane-embedded domain of α7 by that of the related 5-HT ₃A receptor increases the number of sites that need to be occupied to achieve the maximal open-channel lifetime, thus revealing a unique interdependence between the detector and actuator domains of these receptors. The distinctive ability of a single occupancy to elicit a full biological response adapts α7 to volume transmission, a prevalent mechanism of ACh-mediated signaling in the nervous system and nonneuronal cells.

Of the many serotonin receptors, the type 3 receptors (5-HT3R) are the only ionotropic ones, playing a key role in fast synaptic transmission and cognitive and emotional brain function through controlled neuronal excitation. To better understand the various functions of 5-HT3Rs, it is very important to know their expression pattern in the central nervous system (CNS). To date, many distributional studies have shown localized 5-HT3R expression in the brain and spinal cord. However, an accurate pattern of 5-HT3R expression in the CNS remains to be elucidated. To investigate the distribution of 5-HT3R in the mouse brain in detail, we performed immunofluorescent staining using 5-HT3AR-GFP transgenic mice. We found strong 5-HT3AR expression in the olfactory bulb, cerebral cortex, hippocampus, and amygdala; and partial expression in the pons, medulla, and spinal cord. Meanwhile, the thalamus, hypothalamus, and midbrain exhibited a few 5-HT3AR-expressing cells, and no expression was detected in the cerebellum. Further, double-immunostaining using neural markers confirmed that 5-HT3AR is expressed in GABAergic interneurons containing somatostatin or calretinin. In the present study, we built a 5-HT3AR expression map in the mouse brain. Our findings make significant contributions in elucidating the novel functions of 5-HT3R in the CNS.