Self-compassion defuses the aggression triggered by social exclusion.

Social exclusion is a pervasive phenomenon that can have profound psychological consequences, including increased aggression. Self-compassion can promote psychological resilience, which helps individuals cope with challenges and may help mitigate the aggression triggered by social exclusion. This study aims to explore the relationship between self-compassion and aggression in the context of social exclusion from both state and trait perspectives. First, a cross-sectional study (Study 1) was conducted; the findings revealed that social exclusion is associated with higher levels of aggression, while self-compassion is linked to lower levels of social exclusion and aggression. Further division of self-compassion into its constituent components (self-kindness, mindfulness, and common humanity) revealed additional insights into the specific roles played by these factors. Self-kindness and mindfulness were found to moderate the relationship between social exclusion and aggression, while common humanity was observed to mediate this relationship. To determine the causal relationships among variables in further detail, an experimental study (Study 2) was designed. This study utilized a recall writing task to induce feelings of social exclusion and employed self-compassion writing tasks to elicit self-compassionate responses from participants. The results of this experiment indicated that self-compassion can significantly reduce the aggression triggered by social exclusion, thus suggesting that self-compassion may help alleviate the distress caused by individuals' experiences of social exclusion. The findings of this research have important implications for the development of clinical interventions aimed at reducing the adverse effects of social exclusion.

The relationship between self-esteem and aggressive behavior among Chinese adolescents: A moderated chain mediation model.

This study aimed to examine the relationship between adolescent self-esteem and aggressive behavior. Specifically, a moderated chain mediation model was developed to investigate the mediating role of jealousy and self-control and the moderating role of gender. Data were collected from 652 Chinese adolescents who completed the Self-Esteem Scale, Self-Report Jealousy Scale, Self-Control Scale and Aggressive Behavior Questionnaire. Results showed that adolescent self-esteem may significantly negatively affect aggressive behavior by mediating with jealousy and self-control. Moreover, gender possibly moderates the serial mediating effect of jealousy and self-control between adolescent self-esteem and aggressive behavior. The results have important theoretical and practical implications in that these reveal the influencing factors of adolescent aggressive behavior and the pathways to reduce such behavior.

Effect of virtual reality exercise on interventions for patients with Alzheimer's disease: A systematic review.

Virtual reality (VR) interventions are increasingly being used in rehabilitating and treating patients with neurological disorders. This study aimed to explore the effects of VR exercise interventions for patients with Alzheimer's disease (AD). A systematic review of the published literature on randomized controlled trials of VR technology applied to patients with AD was conducted using the preferred reporting entry for systematic reviews and Meta-analysis guidelines. Descriptive analyses were performed to assess the quality of the studies in terms of the characteristics of the included studies, samples, diagnoses, types of VR technologies, subjective and objective levels of immersion, and quality of studies. Eight studies were included, including a pooled sample of 362 patients with AD. A systematic review showed that most studies focused on patients with AD's cognitive and physical functions. The main finding was that VR interventions could help improve cognitive and physical balance in patients with AD. However, future studies should emphasize design and use well-accepted assessment tools to validate the effects of VR interventions further.

Effect of Virtual Reality on Balance Function in Children With Cerebral Palsy: A Systematic Review and Meta-analysis.

Virtual Reality (VR) therapy is popular in treating children with Cerebral Palsy (CP) as a new technology for rehabilitation. Nevertheless, no substantial evidence supporting VR therapy promotion has been developed to date. This study aimed to investigate the effects of VR therapy on balance in children with CP. We conducted a systematic search in PubMed and Web of Science (updated to December 30, 2021). The systematic review and meta-analysis included all randomized controlled trials that included children with CP. A total of 18 RCT studies were eligible for inclusion in the systematic review, and meta-analysis was performed on 16 of them. Results showed that the VR intervention was beneficial for balance (SMD 0.47 [95% CI, SD 0.28, 0.66]). We concluded that VR therapy interventions for children with CP have positive effects. However, cautious implementation is needed in clinical applications.

Altered Processing of Social Emotions in Individuals With Autistic Traits.

Social impairment is a defining phenotypic feature of autism. The present study investigated whether individuals with autistic traits exhibit altered perceptions of social emotions. Two groups of participants (High-AQ and Low-AQ) were recruited based on their scores on the autism-spectrum quotient (AQ). Their behavioral responses and event-related potentials (ERPs) elicited by social and non-social stimuli with positive, negative, and neutral emotional valence were compared in two experiments. In Experiment 1, participants were instructed to view social-emotional and non-social emotional pictures. In Experiment 2, participants were instructed to listen to social-emotional and non-social emotional audio recordings. More negative emotional reactions and smaller amplitudes of late ERP components (the late positive potential in Experiment 1 and the late negative component in Experiment 2) were found in the High-AQ group than in the Low-AQ group in response to the social-negative stimuli. In addition, amplitudes of these late ERP components in both experiments elicited in response to social-negative stimuli were correlated with the AQ scores of the High-AQ group. These results suggest that individuals with autistic traits have altered emotional processing of social-negative emotions.

Processing of expressions by individuals with autistic traits: Empathy deficit or sensory hyper-reactivity?

Individuals with autistic traits display impaired social interaction and communication in everyday life, but the underlying cognitive neural mechanisms remain very unclear and still remain controversial. The mind-blindness hypothesis suggests that social difficulties in individuals with autistic traits are caused by empathy impairment in individuals; however, the intense world theory suggests that these social difficulties are caused by sensory hyper-reactivity and sensory overload, rather than empathy impairment. To further test these two theories, this study investigated event-related potentials (ERPs) to explore the cognitive neural processing of repetitive expressions in individuals with autistic traits. This study employed the Mandarin version of the autism-spectrum quotient (AQ) to assess autistic traits in 2,502 healthy adults. Two subset groups were used, e.g., the participants of a high-AQ group were randomly selected among the 10% of individuals with the highest AQ scores; similarly, the participants in the low-AQ group were randomly selected from the 10% of participants with the lowest AQ scores. In an experiment, three different facial expressions (positive, neutral, or negative) of the same person were presented successively and pseudo-randomly in each trial. Participants needed to define the expression of the face that was presented last. The results showed that compared with the low-AQ group, the high-AQ group exhibited higher P1 amplitudes induced by the second and third presented expressions, as well as higher P3 amplitudes induced by the third presented negative expressions. This indicates that individuals with autistic traits may experience overly strong perception, attention, and cognitive evaluation to repetitive expressions, particularly negative expressions. This result supports the intense world theory more strongly than the mind-blindness hypothesis.

Pain Modulates Responses to Emotional Stimuli.

Pain and emotion are common subjective experiences that play vital roles in daily life. Pain has been clinically confirmed to increase depressive mood. However, little is known about how pain modulates cognitive emotional judgment processing. A better understanding of this may help explain the effect of pain on the development of depressive moods. We recruited 30 adult participants to test their responses to pictures of scenes (Experiment 1) and faces (Experiment 2) that represented happy, neutral, and sad emotions, while experiencing painful (induced via topical capsaicin cream) and control (hand cream) treatments. Results showed that participants in the painful condition showed lower accuracy to emotional scene stimuli and longer reaction times to both emotional scene and face stimuli, relative to the control condition. In addition, the difference values of the reaction times between the painful and control conditions were larger for sad scenes than for happy or neutral scenes. These results suggest that pain alters attentional processing of emotional stimuli, especially with regards to sad scene stimuli, which may explain how painful stimuli affect the development of depressive moods.

Affective and Cognitive Empathy in Pre-teachers With Strong or Weak Professional Identity: An ERP Study.

Pain empathy is influenced by a number of factors. However, few studies have examined the effects of strength of professional identity on pain empathy in pre-service teachers. This study used the event-related potential (ERP) technique, which offers a high temporal resolution, to investigate the neurocognitive mechanisms of pain empathy in pre-teachers with strong or weak professional identity. The N110 and P300 components have been shown to reflect an individual's emotional sharing and cognitive evaluation in pain empathy, respectively. The results of the current study show that pre-teachers with strong professional identity showed a significant difference in N110 amplitudes evoked towards painful and non-painful stimuli; whereas pre-teachers with weak professional identity did not show a significant difference in the amplitudes evoked by the two stimulus types. For the P300 component, pre-teachers with weak professional identity showed a significant difference in the amplitudes evoked towards painful and non-painful stimuli; whereas pre-teachers with strong professional identity did not show a significant difference in the amplitudes evoked by the two stimulus types. Our results indicate that pre-teachers with strong professional identity show a higher level of pain empathy than those with weak professional identity.

Differences in the emotional conflict task between individuals with high and low social adjustment: An ERP study.

To investigate the emotional conflict processing during the processing of emotional stimuli in individuals with different levels of social adjustment through developing an event-related potential (ERP) method, the study used positive words (happy), negative words (disgusted), positive faces and negative faces as experimental materials for a face-word Stroop emotional conflict task, which was completed by 34 participants. For the N2 component, there was a significant difference between the high and low social adjustment groups for the congruent condition; the low social adjustment group evoked more negative amplitude under the congruent condition. Under the incongruent condition, there was a marginally significant difference between the high and low social adjustment groups; the low social adjustment group evoked more negative amplitude under the incongruent condition. For the SP component, there were no significant differences for both the high and low social adjustment group between the congruent and incongruent conditions of emotional conflict. However, within the low social adjustment group, the incongruent evoked more positive amplitude. Our findings indicate that the difference in the emotional conflict process between individuals with high and low social adjustment mainly lies in the early processing stages of emotional information. That is, for both congruent and incongruent emotional stimuli, individuals with high social adjustment showed better emotional conflict monitoring, used less cognitive resources, and had a higher degree of automated processing than those with low social adjustment. During the later stages of emotional conflict processing, individuals with low social adjustment showed poorer conflict processing.

The Effect of Target Sex, Sexual Dimorphism, and Facial Attractiveness on Perceptions of Target Attractiveness and Trustworthiness.

Facial sexual dimorphism has widely demonstrated as having an influence on the facial attractiveness and social interactions. However, earlier studies show inconsistent results on the effect of sexual dimorphism on facial attractiveness judgments. Previous studies suggest that the level of attractiveness might work as a moderating variable among the relationship between sexual dimorphism and facial preference and have often focused on the effect of sexual dimorphism on general attractiveness ratings, rather than concentrating on trustworthiness perception. Male and female participants viewed target male and female faces that varied on attractiveness (more attractive or less attractive) and sexual dimorphism (masculine or feminine). Participants rated the attractiveness of the faces and reported how much money they would give to the target person as a measure of trust. For the facial attractiveness ratings, (a) both men and women participants preferred masculine male faces to feminine male ones under the more attractive condition, whereas preferred feminine male faces to masculine male ones under the less attractive condition; (b) all participants preferred feminine female faces to masculine female ones under the less attractive condition, while there were no differences between feminine female faces and masculine female faces under the more attractive condition. For the target trustworthiness perception, (a) participants showed no preference between masculine male faces and feminine male faces, neither under the more attractive condition nor the less attractiveness condition; (b) however, all the participants preferred masculine female faces over feminine female faces under the more attractive condition, exhibiting no preference between feminine female faces and masculine female faces under the less attractive condition. These findings suggest that the attractiveness of facial stimulus may be a reason to interpret the inconsistent results from the previous studies, which focused on the effect of facial sexual dimorphism on the facial attractiveness. Furthermore, implications about the effect of target facial sexual dimorphism on participants' trustworthiness perception were discussed.

From crystal structure of α-conotoxin GIC in complex with Ac-AChBP to molecular determinants of its high selectivity for α3ß2 nAChR.

Acetylcholine binding proteins (AChBPs) are unique spatial homologs of the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), and they reproduce some pharmacological properties of nAChRs. X-ray crystal structures of AСhBP in complex with α-conotoxins provide important insights into the interactions of α-conotoxins with distinct nAChR subtypes. Although considerable efforts have been made to understand why α-conotoxin GIC is strongly selective for α3ß2 nAChR, this question has not yet been solved. Here we present the structure of α-conotoxin GIC in complex with Aplysia californica AChBP (Ac-AChBP) at a resolution of 2.1 Å. Based on this co-crystal structure complemented with molecular docking data, we suggest the key residues of GIC in determining its high affinity and selectivity for human α3ß2 vs α3ß4 nAChRs. These suggestions were checked by radioligand and electrophysiology experiments, which confirmed the functional role of detected contacts for GIC interactions with Ac-AChBP and α3ß2 nAChR subtypes. While GIC elements responsible for its high affinity binding with Ac-AChBP and α3ß2 nAChR were identified, our study also showed the limitations of computer modelling in extending the data from the X-ray structures of the AChBP complexes to all nAChR subtypes.

Anti-hypersensitive effect of intramuscular administration of αO-conotoxin GeXIVA[1,2] and GeXIVA[1,4] in rats of neuropathic pain.

αO-conotoxin GeXIVA (GeXIVA) is a potent antagonist of α9α10 nicotinic acetylcholine receptors (nAChRs), which has four Cys residues and three disulfide isomers. Among the 3 isomers, both GeXIVA[1,2] (bead isomer) and GeXIVA[1,4] (ribbon isomer) showed potent block on α9α10 nAChRs with close low nanomolar IC50s. Here we report that anti-hypersensitive effects of the bead and ribbon isomers in the chronic constriction injury (CCI) model of neuropathic pain and acute pain model of tail flick test. Treatment was started and continued for 7 or 14days after the development of hyperalgesia which was induced by CCI surgery. GeXIVA[1,2] and GeXIVA[1,4] significantly reduced mechanical allodynia in CCI rats without tolerance, in which GeXIVA[1,2] remained up to two weeks after intramuscular administration of the toxins was ceased. The pain reliever effect of GeXIVA[1,2] on neuropathic rats was slightly better than GeXIVA[1,4]. The two isomers did not suppress the acute thermal pain behaviors significantly when they were tested in the tail flick model by intramuscular bolus injection. Both GeXIVA[1,2] and GeXIVA[1,4] had no significant effect on performance of rats in the accelerating rotarod test after intramuscular injections. This suggests that αO-conotoxin GeXIVA[1,2] and GeXIVA[1,4] may offer new strategies to the treatment of neuropathic pain.

Cloning, synthesis, and characterization of αO-conotoxin GeXIVA, a potent α9α10 nicotinic acetylcholine receptor antagonist.

We identified a previously unidentified conotoxin gene from Conus generalis whose precursor signal sequence has high similarity to the O1-gene conotoxin superfamily. The predicted mature peptide, αO-conotoxin GeXIVA (GeXIVA), has four Cys residues, and its three disulfide isomers were synthesized. Previously pharmacologically characterized O1-superfamily peptides, exemplified by the US Food and Drug Administration-approved pain medication, ziconotide, contain six Cys residues and are calcium, sodium, or potassium channel antagonists. However, GeXIVA did not inhibit calcium channels but antagonized nicotinic AChRs (nAChRs), most potently on the α9α10 nAChR subtype (IC50 = 4.6 nM). Toxin blockade was voltage-dependent, and kinetic analysis of toxin dissociation indicated that the binding site of GeXIVA does not overlap with the binding site of the competitive antagonist α-conotoxin RgIA. Surprisingly, the most active disulfide isomer of GeXIVA is the bead isomer, comprising, according to NMR analysis, two well-resolved but uncoupled disulfide-restrained loops. The ribbon isomer is almost as potent but has a more rigid structure built around a short 310-helix. In contrast to most α-conotoxins, the globular isomer is the least potent and has a flexible, multiconformational nature. GeXIVA reduced mechanical hyperalgesia in the rat chronic constriction injury model of neuropathic pain but had no effect on motor performance, warranting its further investigation as a possible therapeutic agent.

Key residues in the nicotinic acetylcholine receptor ß2 subunit contribute to α-conotoxin LvIA binding.

α-Conotoxin LvIA (α-CTx LvIA) is a small peptide from the venom of the carnivorous marine gastropod Conus lividus and is the most selective inhibitor of α3ß2 nicotinic acetylcholine receptors (nAChRs) known to date. It can distinguish the α3ß2 nAChR subtype from the α6ß2* (* indicates the other subunit) and α3ß4 nAChR subtypes. In this study, we performed mutational studies to assess the influence of residues of the ß2 subunit versus those of the ß4 subunit on the binding of α-CTx LvIA. Although two ß2 mutations, α3ß2[F119Q] and α3ß2[T59K], strongly enhanced the affinity of LvIA, the ß2 mutation α3ß2[V111I] substantially reduced the binding of LvIA. Increased activity of LvIA was also observed when the ß2-T59L mutant was combined with the α3 subunit. There were no significant difference in inhibition of α3ß2[T59I], α3ß2[Q34A], and α3ß2[K79A] nAChRs when compared with wild-type α3ß2 nAChR. α-CTx LvIA displayed slower off-rate kinetics at α3ß2[F119Q] and α3ß2[T59K] than at the wild-type receptor, with the latter mutant having the most pronounced effect. Taken together, these data provide evidence that the ß2 subunit contributes to α-CTx LvIA binding and selectivity. The results demonstrate that Val(111) is critical and facilitates LvIA binding; this position has not previously been identified as important to binding of other 4/7 framework α-conotoxins. Thr(59) and Phe(119) of the ß2 subunit appear to interfere with LvIA binding, and their replacement by the corresponding residues of the ß4 subunit leads to increased affinity.

A novel α4/7-conotoxin LvIA from Conus lividus that selectively blocks α3ß2 vs. α6/α3ß2ß3 nicotinic acetylcholine receptors.

This study was performed to discover and characterize the first potent α3ß2-subtype-selective nicotinic acetylcholine receptor (nAChR) ligand. A novel α4/7-conotoxin, α-CTxLvIA, was cloned from Conus lividus. Its pharmacological profile at Xenopus laevis oocyte-expressed rat nAChR subtypes was determined by 2-electrode voltage-clamp electrophysiology, and its 3-dimensional (3D) structure was determined by NMR spectroscopy. α-CTx LvIA is a 16-aa C-terminally-amidated peptide with 2-disulfide bridges. Using rat subunits expressed in Xenopus oocytes, we found the highest affinity of α-CTxLvIA was for α3ß2 nAChRs (IC50 8.7 nM), where blockade was reversible within 2 min. IC50 values were >100 nM at α6/α3ß2ß3, α6/α3ß4, and α3ß4 nAChRs, and ≥3 µM at all other subtypes tested. α3ß2 vs. α6ß2 subtype selectivity was confirmed for human-subunit nAChRs with much greater preference (300-fold) for α3ß2 over α6ß2 nAChRs. This is the first α-CTx reported to show high selectivity for human α3ß2 vs. α6ß2 nAChRs. α-CTxLvIA adopts two similarly populated conformations water: one (assumed to be bioactive) is highly structured, whereas the other is mostly random coil in nature. Selectivity differences with the similarly potent, but less selective, α3ß2 nAChR antagonist α-CTx PeIA probably reside within the three residues, which differ in loop 2, given their otherwise similar 3D structures. α4/7-CTx LvIA is a new, potent, selective α3ß2 nAChR antagonist, which will enable detailed studies of α3ß2 nAChR structure, function, and physiological roles.

Characterization of a novel α-conotoxin TxID from Conus textile that potently blocks rat α3ß4 nicotinic acetylcholine receptors.

The α3ß4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an α-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat α3ß4 nAChRs with a 12.5 nM IC50, which places it among the most potent α3ß4 nAChR antagonists. TxID also blocked the closely related α6/α3ß4 with a 94 nM IC50 but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular α-CTx fold but with different surface charge distribution to other 4/6 family members. α-CTx TxID is a novel tool with which to probe the structure and function of α3ß4 nAChRs.

Expression and secretion of functional recombinant µO-conotoxin MrVIB-His-tag in Escherichia coli.

µO-conotoxin MrVIB is a 31-amino acid peptide containing three disulfide bonds isolated from the venom of Conus marmoreus, which is a selective antagonist of voltage-gated sodium channel (VGSC) Nav1.8 and has a long-lasting analgesic activity. Drug development of MrVIB has long been hindered over 15 years by difficult chemical synthesis and oxidative folding. Herein we describe a different approach based on the recombinant expression of gene MrVIB in Escherichia coli. A secretion vector pET22b(+)-MrVIB fused with pelB leader signal peptide and His-tag was constructed, which was transformed into BL21 (DE3) strain of E. coli. The recombinant conotoxin MrVIB-His-tag (rMrVIB-His) was successfully expressed and secreted into the periplasmic space of BL21 (DE3) cells. The pelB leader signal peptide was properly cleaved and three disulfide bonds were also formed properly to yield biological active rMrVIB-His. Folded rMrVIB-His in the periplasmic fraction was isolated with a Ni-NTA affinity column, which was further purified using reverse-phase high-performance liquid chromatography (RP-HPLC) and identified by liquid chromatography/mass spectrometry-ion trap-time of flight mass spectrometry (LC/MS-IT-TOF). Biological activity assay of rMrVIB-His showed it had good analgesic effects in three pain models.

A novel inhibitor of α9α10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily.

Conotoxins (CTxs) selectively target a range of ion channels and receptors, making them widely used tools for probing nervous system function. Conotoxins have been previously grouped into superfamilies according to signal sequence and into families based on their cysteine framework and biological target. Here we describe the cloning and characterization of a new conotoxin, from Conus vexillum, named αB-conotoxin VxXXIVA. The peptide does not belong to any previously described conotoxin superfamily and its arrangement of Cys residues is unique among conopeptides. Moreover, in contrast to previously characterized conopeptide toxins, which are expressed initially as prepropeptide precursors with a signal sequence, a ''pro'' region, and the toxin-encoding region, the precursor sequence of αB-VxXXIVA lacks a ''pro'' region. The predicted 40-residue mature peptide, which contains four Cys, was synthesized in each of the three possible disulfide arrangements. Investigation of the mechanism of action of αB-VxXXIVA revealed that the peptide is a nicotinic acetylcholine receptor (nAChR) antagonist with greatest potency against the α9α10 subtype. (1)H nuclear magnetic resonance (NMR) spectra indicated that all three αB-VxXXIVA isomers were poorly structured in aqueous solution. This was consistent with circular dichroism (CD) results which showed that the peptides were unstructured in buffer, but adopted partially helical conformations in aqueous trifluoroethanol (TFE) solution. The α9α10 nAChR is an important target for the development of analgesics and cancer chemotherapeutics, and αB-VxXXIVA represents a novel ligand with which to probe the structure and function of this protein.

Characterization of a novel α-conotoxin from conus textile that selectively targets α6/α3ß2ß3 nicotinic acetylcholine receptors.

α6ß2 Nicotinic acetylcholine receptors (nAChRs) expressed by dopaminergic neurons in the CNS are potential therapeutic targets for the treatment of several neuropsychiatric diseases, including nicotine addiction and Parkinson disease. However, recent studies indicate that the α6 subunit can also associate with the ß4 subunit to form α6ß4 nAChRs that are difficult to pharmacologically distinguish from α6ß2, α3ß4, and α3ß2 subtypes. The current study characterized a novel 16-amino acid α-conotoxin (α-CTx) TxIB from Conus textile whose sequence is GCCSDPPCRNKHPDLC-amide as deduced from gene cloning. The peptide and an analog with an additional C-terminal glycine were chemically synthesized and tested on rat nAChRs heterologously expressed in Xenopus laevis oocytes. α-CTx TxIB blocked α6/α3ß2ß3 nAChR with an IC(50) of 28 nm. In contrast, the peptide showed little or no block of other tested subtypes at concentrations up to 10 µm. The three-dimensional solution structure of α-CTx TxIB was determined using NMR spectroscopy. α-CTx TxIB represents a uniquely selective ligand for probing the structure and function of α6ß2 nAChRs.

Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel microsite of the alpha3beta2 nicotinic receptor.

Different nicotinic acetylcholine receptor (nAChR) subtypes are implicated in learning, pain sensation, and disease states, including Parkinson disease and nicotine addiction. alpha-Conotoxins are among the most selective nAChR ligands. Mechanistic insights into the structure, function, and receptor interaction of alpha-conotoxins may serve as a platform for development of new therapies. Previously characterized alpha-conotoxins have a highly conserved Ser-Xaa-Pro motif that is crucial for potent nAChR interaction. This study characterized the novel alpha-conotoxin LtIA, which lacks this highly conserved motif but potently blocked alpha3beta2 nAChRs with a 9.8 nm IC(50) value. The off-rate of LtIA was rapid relative to Ser-Xaa-Pro-containing alpha-conotoxin MII. Nevertheless, pre-block of alpha3beta2 nAChRs with LtIA prevented the slowly reversible block associated with MII, suggesting overlap in their binding sites. nAChR beta subunit ligand-binding interface mutations were used to examine the >1000-fold selectivity difference of LtIA for alpha3beta2 versus alpha3beta4 nAChRs. Unlike MII, LtIA had a >900-fold increased IC(50) value on alpha3beta2(F119Q) versus wild type nAChRs, whereas T59K and V111I beta2 mutants had little effect. Molecular docking simulations suggested that LtIA had a surprisingly shallow binding site on the alpha3beta2 nAChR that includes beta2 Lys-79. The K79A mutant disrupted LtIA binding but was without effect on an LtIA analog where the Ser-Xaa-Pro motif is present, consistent with distinct binding modes.