Teneurin C-terminal Associated Peptide Research Articles

Teneurin C-terminal associated peptide (TCAP)-1 attenuates the development and expression of naloxone-precipitated morphine withdrawal in male Swiss Webster mice.

Corticotropin-releasing factor (CRF), the apical stress-inducing hormone, exacerbates stress and addictive behaviors. TCAP-1 is a peptide that directly inhibits both CRF-mediated stress and addiction-related behaviors; however, the direct action of TCAP-1 on morphine withdrawal-associated behaviors has not previously been examined. To determine whether TCAP-1 administration attenuates behavioral and physiological consequences of morphine withdrawal in mice. Mice were administered via subcutaneous route TCAP-1 either before or after initial morphine exposure, after which jumping behavior was quantified to assess the effects of TCAP-1 on naloxone-precipitated morphine withdrawal. As a comparison, mice were treated with nonpeptide CRF1 receptor antagonist CP-154,526. In one experiment, plasma corticosterone (CORT) was also measured as a physiological stress indicator. Pretreatment with TCAP-1 (10-250 nmol/kg) before morphine treatment significantly inhibited the development of naloxone-precipitated withdrawal. TCAP-1 (250-500 nmol/kg) treatment administered after morphine treatment attenuated the behavioral expression of naloxone-precipitated withdrawal. TCAP-1 (250 nmol/kg) treatment during morphine treatment was more effective than the optimal dosing of CP-154,526 (20mg/kg) at suppressing the behavioral expression of naloxone-precipitated withdrawal, despite similar reduction of withdrawal-induced plasma CORT level increases. These findings establish TCAP-1 as a potential therapeutic candidate for the prevention and treatment of morphine withdrawal.

A novel role for Teneurin C-terminal Associated Peptide (TCAP) in the regulation of cardiac activity in the Sydney rock oyster, Saccostrea glomerata.

Teneurin C-terminal associated peptide (TCAP) is an ancient bioactive peptide that is highly conserved in metazoans. TCAP administration reduces cellular and behavioural stress in vertebrate and urochordate models, yet despite numerous studies in higher animals, there is limited knowledge of its role in invertebrates. In particular, there are no studies on TCAP's effects on the heart of any metazoan, which is a critical organ in the stress response. We used the Sydney rock oyster (SRO) as an invertebrate model to investigate a potential role for sroTCAP in regulating cardiac activity, including during stress. sroTCAP is localized to the neural innervation network of the SRO heart, and suggested binding with various heart proteins related to metabolism and stress, including SOD, GAPDH and metabotropic glutamate receptor. Intramuscular injection of sroTCAP (10 pmol) significantly altered the expression of heart genes that are known to regulate remodelling processes under different conditions, and modulated several gene families responsible for stress mitigation. sroTCAP (1 and 10 pmol) was shown to cause transient bradycardia (heart rate was reduced by up to 63% and for up to 40min post-administration), indicative of an unstressed state. In summary, this study has established a role for a TCAP in the regulation of cardiac activity through modulation of physiological and molecular components associated with energy conservation, stress and adaptation. This represents a novel function for TCAP and may have implications for higher-order metazoans.

Skeletal muscle metabolism and contraction performance regulation by teneurin C-terminal-associated peptide-1.

Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism in rats. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 in the C2C12 mouse skeletal cell line shows that TCAP stimulates an LPHN-dependent cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism that regulates the energy requirements and performance of skeletal muscle.

Distal extracellular teneurin region (teneurin C-terminal associated peptide; TCAP) possesses independent intracellular calcium regulating actions, in vitro: A potential antagonist of corticotropin-releasing factor (CRF)

Teneurin C-terminal associated peptides (TCAP) are natural bioactive peptides that possess anxiety-reducing roles in animals, in vivo, and increase cell viability, in vitro. Although these peptides have some primary structural similarity to corticotropin-releasing factor (CRF), they are derived from the distal extracellular region of the teneurin transmembrane protein where they may act as separate soluble peptides after auto-catalytic cleavage from the teneurin protein following interaction with the cognate teneurin receptor, latrophilin (ADGRL), or expressed as a separate mRNA. However, although the signal transduction mechanism of TCAP in neurons has not been established, previous studies indicate an association with the intracellular calcium flux. Therefore, in this study, we have characterized the TCAP-mediated calcium response in hypothalamic cell lines using single-cell calcium methods with pharmacological antagonists to identify potential calcium channels, in vitro. Under normal circumstances, TCAP-1 reduces cytosolic calcium concentrations by uptake into the mitochondria and efflux through the plasma membrane independently of the teneurins. In doing so, TCAP-1 could inhibit the potential ‘stress’ -inducing actions of CRF.

Teneurin and TCAP Phylogeny and Physiology: Molecular Analysis, Immune Activity, and Transcriptomic Analysis of the Stress Response in the Sydney Rock Oyster (Saccostrea glomerata) Hemocytes.

Teneurin C-terminal associated peptide (TCAP) is an ancient bioactive peptide that is highly conserved in metazoans. TCAP administration reduces cellular and behavioral stress in vertebrate and urochordate models. There is little information for invertebrates regarding the existence or function of a TCAP. This study used the Sydney rock oyster (SRO) as a molluscan model to characterize an invertebrate TCAP, from molecular gene analysis to its physiological effects associated with hemocyte phagocytosis. We report a single teneurin gene (and 4 teneurin splice variants), which encodes a precursor with TCAP that shares a vertebrate-like motif, and is similar to that of other molluscan classes (gastropod, cephalopod), arthropods and echinoderms. TCAP was identified in all SRO tissues using western blotting at 1-2 different molecular weights (~22 kDa and ~37kDa), supporting precursor cleavage variation. In SRO hemolymph, TCAP was spatially localized to the cytosol of hemocytes, and with particularly high density immunoreactivity in granules. Based on ‘pull-down’ assays, the SRO TCAP binds to GAPDH, suggesting that TCAP may protect cells from apoptosis under oxidative stress. Compared to sham injection, the intramuscular administration of TCAP (5 pmol) into oysters modulated their immune system by significantly reducing hemocyte phagocytosis under stress conditions (low salinity and high temperature). TCAP administration also significantly reduced hemocyte reactive oxygen species production at ambient conditions and after 48 h stress, compared to sham injection. Transcriptomic hemocyte analysis of stressed oysters administered with TCAP demonstrated significant changes in expression of genes associated with key metabolic, protective and immune functions. In summary, this study established a role for TCAP in oysters through modulation of physiological and molecular functions associated with energy conservation, stress and cellular defense.

Role of Teneurin C-Terminal Associated Peptides (TCAP) on Intercellular Adhesion and Communication.

The teneurin C-terminal associated peptides (TCAP) are encoded by the terminal exon of all metazoan teneurin genes. Evidence supports the liberation of a soluble TCAP peptide either by proteolytic cleavage from the mature transmembrane teneurin protein or by a separately transcribed mRNA. Synthetic versions of TCAP, based on its genomic structure, are efficacious at regulating intercellular communication by promoting neurite outgrowth and increasing dendritic spine density in vitro and in vivo in rodent models. This is achieved through cytoskeletal re-arrangement and metabolic upregulation. The putative receptors for TCAPs are the latrophilin (LPHN) family of adhesion G-protein coupled receptors, which facilitate TCAP’s actions through G-proteins associated with cAMP and calcium-regulating signalling pathways. The teneurin/TCAP and latrophilin genes are phylogenetically ancient, likely serving primitive functions in cell adhesion and energy regulation which have been since adapted for a more complex role in synaptogenesis in vertebrate nervous systems.

Distal Extracellular Teneurin Region (Teneurin C-Terminal Associated Peptide; TCAP) Possesses Independent Intracellular Calcium Regulating Actions, in Vitro: A Novel Antagonist of Corticotropin-Releasing Factor (CRF)

Distal Extracellular Teneurin Region (Teneurin C-Terminal Associated Peptide; TCAP) Possesses Independent Intracellular Calcium Regulating Actions, in Vitro: A Novel Antagonist of Corticotropin-Releasing Factor (CRF)

Teneurin C-Terminal Associated Peptide (TCAP)-3 Increases Metabolic Activity in Zebrafish

Teneurin C-terminal associated peptides (TCAP), bioactive peptides located on the C-terminal end of teneurin proteins, have been shown to regulate stress axis functions due to the high conservation between TCAP and corticotropin releasing factor (CRF). Additionally, recent work demonstrated that TCAP can increase metabolism in rats via glucose metabolism. These metabolic actions are not well described in other organisms, including teleosts. Here we investigated the expression of a tcap isoform, tcap-3, and the potential role of TCAP-3 as a regulator of metabolism across zebrafish life-stages. Using pcr-based analyses, tcap-3 appears to be independently transcribed, in relation to teneurin-3, in muscle tissue of adult zebrafish. Resazurin, respirometry chambers, and mitochondrial metabolism analyses were used to study the metabolic effects of synthetic rainbow trout TCAP-3 (rtTCAP-3) in larval and adult zebrafish. Overall, metabolic activity was enhanced by 48 h of rtTCAP-3 treatment in larvae (bath immersion) and adults (intraperitoneal injections). This metabolic activity increase was due to mitochondrial uncoupling, as mitochondrial respiration increase by rtTCAP-3 was due to proton leak. Additionally, rtTCAP-3 protected larval fish from reduced metabolic activity induced by low temperatures. Subsequently, rtTCAP-3 increased metabolic output in adult zebrafish subjected to accelerated swimming speeds, demonstrating the potent role of rtTCAP-3 in zebrafish metabolism regulation during metabolic challenges. Collectively, these results demonstrate the conserved roles for rtTCAP-3 as a metabolic activator in zebrafish.

Corticotropin-Releasing Factor: An Ancient Peptide Family Related to the Secretin Peptide Superfamily.

Corticotropin-releasing factor (CRF) is the hypothalamic releasing peptide that regulates the hypothalamic-pituitary-adrenal/inter-renal (HPA/I) axis in vertebrates. Over the last 25 years, there has been considerable discussion on its paralogs genes, urotensin-I/urocortin-1, and urocortins-2 and-3 and their subsequent role in the vertebrate stress response. Phylogenetically, the CRF family of peptides also belong to the diverse assemblage of Secretin- and Calcitonin-based peptides as evidenced by comparative-based studies of both their ligand and G-protein-coupled receptor (GPCR) structures. Despite this, the common origin of this large assemblage of peptides has not been ascertained. An unusual peptide, teneurin-C-terminal associated peptide (TCAP), reported in 2004, comprises the distal extracellular tip of the teneurin transmembrane proteins. Further studies indicated that this teneurin region binds to the latrophilin family of GPCRs. Initially thought to be a member of the Secretin GPCR family, evidence indicates that the latrophilins are a member of the Adhesion family of GPCRs and are related to the common ancestor of both Adhesion and Secretin GPCR families. In this study, we posit that TCAP may be a distantly related ancestor of the CRF-Calcitonin-Secretin peptide family and evolved near the base of metazoan phylogeny.

Information Processing in Affective Disorders: Did an Ancient Peptide Regulating Intercellular Metabolism Become Co-Opted for Noxious Stress Sensing?

Affective disorders arise in stressful situations from aberrant sensory information integration that affects energetic nutrient (i.e., glucose) utilization to the cognitive centers of the brain. Because energy flow is mediated by molecular signals and receptors that evolved before the first complex brains, the phylogenetically oldest signaling systems are essential in the etiology of affective disorders. The corticotropin-releasing factor (CRF) peptide subfamily is a phylogenetically old metazoan peptide family and is pivotal for regulating organismal energy response associated with stress. Highly conserved, both the CRF peptide family and its receptors possess a structural relationship to the teneurins, and their receptors, latrophilins, respectively. The CRF homologous region of teneurin is defined as the "teneurin C-terminal associated peptide" (TCAP) and antagonizes CRF action, regulates mitochondrial energy production, and is anxiolytic in vivo. Here, it is postulated that TCAP represents an ancient peptide that mediates intercellular information transfer of stressful and noxious events by regulating energy utilization among neurons.

Synthetic Peptides as Therapeutic Agents: Lessons Learned From Evolutionary Ancient Peptides and Their Transit Across Blood-Brain Barriers.

Peptides play a major role in the transmission of information to and from the central nervous system. However, because of their structural complexity, the development of pharmacological peptide-based therapeutics has been challenged by the lack of understanding of endogenous peptide evolution. The teneurin C-terminal associated peptides (TCAP) possess many of the required attributes of a practical peptide therapeutic. TCAPs, associated with the teneurin transmembrane proteins that bind to the latrophilins, members of the Adhesion family of G-protein-coupled receptors (GPCR). Together, this ligand-receptor unit plays an integral role in synaptogenesis, neurological development, and maintenance, and is present in most metazoans. TCAP has structural similarity to corticotropin-releasing factor (CRF), and related peptides, such as calcitonin and the secretin-based peptides and inhibits the (CRF)-associated stress response. Latrophilins are structurally related to the secretin family of GPCRs. TCAP is a soluble peptide that crosses the blood-brain barrier and regulates glucose transport into the brain. We posit that TCAP represents a phylogenetically older peptide system that evolved before the origin of the CRF-calcitonin-secretin clade of peptides and plays a fundamental role in the regulation of cell-to-cell energy homeostasis. Moreover, it may act as a phylogenetically older peptide system that evolved as a natural antagonist to the CRF-mediated stress response. Thus, TCAP's actions on the CNS may provide new insights into the development of peptide therapeutics for the treatment of CNS disorders.

Activity of the Carboxy-Terminal Peptide Region of the Teneurins and Its Role in Neuronal Function and Behavior in Mammals.

Teneurin C-terminal associated peptides (TCAPs) are an evolutionarily ancient family of 40- to 41-residue bioactive peptides located on the extracellular end of each of the four teneurin transmembrane proteins. TCAP-1 may exist as a tethered peptide at the teneurin-1 carboxy end or as an independent peptide that is either released via post-transcriptional cleavage from its teneurin-1 pro-protein or independently expressed as its own mRNA. In neurons, soluble TCAP-1 acts as a paracrine factor to regulate cellular activity and neuroplastic interactions. In vitro studies indicate that, by itself, synthetic TCAP-1 promotes neuron growth and protects cells from chemical insult. In vivo, TCAP-1 increases hippocampal neuron spine density, reduces stress-induced behavior and ablates cocaine-seeking behaviors. Together, these studies suggest that the physiological effects of TCAP-1 are a result of an inhibition of corticotropin-releasing factor (CRF) activity leading to increased energy production. This hypothesis is supported by in vivo functional positron emissions tomography studies, which demonstrate that TCAP-1 significantly increases glucose uptake in rat brain. Complimentary in vitro studies show that enhanced glucose uptake is the result of TCAP-1-induced insertion of the glucose transporter into the neuronal plasma membrane, leading to increased glucose uptake and ATP production. Interestingly, TCAP-1-mediated glucose uptake occurs through a novel insulin-independent pathway. This review will focus on examining the role of TCAP on neuronal energy metabolism in the central nervous system.

Wnt Signaling Upregulates Teneurin-3 Expression via Canonical and Non-canonical Wnt Pathway Crosstalk.

Teneurins (Tens) are a highly conserved family of proteins necessary for cell-cell adhesion. Tens can be cleaved, and some of their proteolytic products, such as the teneurin c-terminal associated-peptide (TCAP) and the intracellular domain (ICD), have been demonstrated to be biologically active. Although Tens are considered critical for central nervous system development, they have also been demonstrated to play important roles in adult tissues, suggesting a potential link between their deregulation and various pathological processes, including neurodegeneration and cancer. However, knowledge regarding how Ten expression is modulated is almost absent. Relevantly, the functions of Tens resemble several of the effects of canonical and non-canonical Wnt pathway activation, including the effects of the Wnt pathways on neuronal development and function as well as their pivotal roles during carcinogenesis. Accordingly, in this initial study, we decided to evaluate whether Wnt signaling can modulate the expression of Tens. Remarkably, in the present work, we used a specific inhibitor of porcupine, the key enzyme for Wnt ligand secretion, to not only demonstrate the involvement of Wnt signaling in regulating Ten-3 expression for the first time but also reveal that Wnt3a, a canonical Wnt ligand, increases the expression of Ten-3 through a mechanism dependent on the secretion and activity of the non-canonical ligand Wnt5a. Although our work raises several new questions, our findings seem to demonstrate the upregulation of Ten-3 by Wnt signaling and also suggest that Ten-3 modulation is possible because of crosstalk between the canonical and non-canonical Wnt pathways.

Teneurins and Teneurin C-Terminal Associated Peptide (TCAP) in Metabolism: What's Known in Fish?

Teneurins have well established roles in function and maintenance of the central nervous systems of vertebrates. In addition, teneurin c-terminal associated peptide (TCAP), a bioactive peptide found on the c-terminal portion of teneurins, has been shown to regulate glucose metabolism. Although, the majority of research conducted on the actions of teneurins and TCAPs has strictly focused on neurological systems in rodents, TCAP was first identified in rainbow trout after screening trout hypothalamic cDNA. This suggests a conserved functional role of TCAP across vertebrates, however, the current depth of literature on teneurins and TCAPs in fish is limited. In addition, the overall function of TCAP in regulating metabolism is unclear. This review will highlight work that has been conducted specifically in fish species in relation to the teneurin system and metabolism in order to identify areas of research that are needed for future work.

Teneurin C-Terminal Associated Peptide (TCAP)-1 and Latrophilin Interaction in HEK293 Cells: Evidence for Modulation of Intercellular Adhesion

The teneurins are a family of four transmembrane proteins essential to intercellular adhesion processes, and are required for the development and maintenance of tissues. The Adhesion G protein-coupled receptor (GPCR) subclass latrophilins (ADGRL), or simply the latrophilins (LPHN), are putative receptors of the teneurins and act, in part, to mediate intercellular adhesion via binding with the teneurin extracellular region. At the distal tip of the extracellular region of each teneurin lies a peptide sequence termed the teneurin C-terminal associated peptide (TCAP). TCAP-1, associated with teneurin-1, is itself bioactive, suggesting that TCAP is a critical functional region of teneurin. However, the role of TCAP-1 has not been established with respect to its ability to interact with LPHN to induce downstream effects. To establish that TCAP-1 binds to LPHN1, a FLAG-tagged hormone binding domain (HBD) of LPHN1 and a GFP-tagged TCAP-1 peptide were co-expressed in HEK293 cells. Both immunoreactive epitopes were co-localized as a single band after immunoprecipitation, indicating an association between the two proteins. Moreover, fluorescent co-labeling occurred at the plasma membrane of LPHN1 over-expressing cells when treated with a FITC-tagged TCAP-1 variant. Expression of LPHN1 and treatment with TCAP-1 modulated the actin-based cytoskeleton in these cells in a manner consistent with previously reported actions of TCAP-1 and affected the overall morphology and aggregation of the cells. This study indicates that TCAP-1 may associate directly with LPHN1 and could play a role in the modulation of cytoskeletal organization and intercellular adhesion and aggregation via this interaction.

A novel role of the corticotrophin-releasing hormone regulating peptide, teneurin C-terminal associated peptide 1, on glucose uptake into the brain.

Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signalling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotrophin-releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurones, where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy-dependent, this suggests that TCAP has the potential to regulate glucose uptake because glucose is the primary energy substrate in brain, and neurones require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of the present study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated 18 F-deoxyglucose (FDG) uptake into brain tissue was assessed in male wild-type Wistar rats by functional positron emission tomography. TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3days and decreased blood glucose after 1week. This is corroborated by a decreased serum concentration of insulin and an increased serum concentration of glucagon. In immortalised hypothalamic neurones, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and mitogen-activated protein kinase/ERK phosphorylation events. Taken together, these data demonstrate that TCAP-1 increases glucose metabolism in neurones, and may represent a peptide signalling agent that regulated glucose uptake before insulin and related peptides.

Teneurin-2 presence in rat and human odontoblasts.

Teneurins are transmembrane proteins consisting of four paralogues (Ten-1-4), notably expressed in the central nervous system during development. All teneurins contain a bioactive peptide in their carboxyl terminal named teneurin C-terminal associated peptide (TCAP). The present study analyzed the detailed distribution of teneurin-2-like immunoreactive (Ten-2-LI) cells in developing and mature rat molar teeth, as well as in mature human dental pulps. Ten-2 and TCAP-2 genic expressions were also evaluated in rat and human dental pulps. Finally, Ten-2-LI cells were analyzed during the repair process after dentin-pulp complex injury in rat lower molar teeth. For this, histological sections of rat molar teeth and human dental pulps were submitted to immunohistochemical techniques, while total RNA from developing rat teeth and mature human dental pulps were submitted to conventional RT-PCR. Ten-2-LI cells were evident in the initial bell stage of rat molar teeth development, especially in ectomesenchymal cells of the dental papilla. Ten-2-LI odontoblasts showed strong immunoreactivity in rat and human mature teeth. Ten-2 and TCAP-2 genic expressions were confirmed in rat and human dental pulps. Dentin-pulp complex injury resulted in a decrease of Ten-2-LI odontoblasts after traumatic injury. Interestingly, Ten-2-LI cells were also evident in the pulp cell-rich zone in all postoperative days. In conclusion, Ten-2-LI presence in rat and human odontoblasts was demonstrated for the first time and Ten-2/TCAP-2 genic expressions were confirmed in rat and human dental pulps. Furthermore, it was revealed that Ten-2-LI rat odontoblasts can be modulated during the regenerative process.

Expression and actions of corticotropin-releasing factor/diuretic hormone-like peptide (CDLP) and teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: Antagonism of the feeding response

Teneurin C-terminal associated peptide (TCAP) is a neuropeptide that bears some structural similarity to the corticotropin-releasing factor (CRF) family of peptides. TCAP and CRF are both implicated in the regulation of stress-related behaviors, as established in rodent models. However, in vertebrates, both TCAP and CRF possess three additional paralogous forms making vertebrate models difficult to assess with respect to TCAP-CRF interaction. As a urochordate, this species possesses single homologs of TCAP and of a CRF/Diuretic-like peptide (CDLP) in the genome, thereby establishing Ciona intestinalis as an excellent model organism to examine the interaction of these peptide systems. However, the lack of C. intestinalis synthetic peptides and specific antisera has complicated experimentation. We, therefore, prepared synthetic versions of CDLP and TCAP to prepare specific antisera and to investigate their bioactivity in this species. To analyze stress-related behaviors, a novel behavioral assay was used to characterize different types of contraction-based behaviors, using buccal opening contractions, cloacal opening contractions, lateral contractions, longitudinal contractions and expulsions. Protein and mRNA expression data indicate that the mature versions of both peptides are present in a number of tissues. With respect to behavioral activity, both TCAP- and CDLP-treated animals had distinct contraction profiles under ambient conditions. Moreover, food stimulation tests revealed that whereas CDLP-treated animals displayed a strong expulsion behavior in response to feeding, TCAP-treated animals did not show this effect. These actions are consistent with previous studies done in vertebrates.

Ancient interaction between the teneurin C-terminal associated peptides (TCAP) and latrophilin ligand-receptor coupling: a role in behavior

Teneurins are multifunctional transmembrane proteins that are found in all multicellular animals and exist as four paralogous forms in vertebrates. They are highly expressed in the central nervous system, where they exert their effects, in part, by high-affinity binding to latrophilin (LPHN), a G-protein coupled receptor (GPCR) related to the adhesion and secretin GPCR families. The teneurin C-terminal associated peptides (TCAPs) are encoded by the terminal exon of all four teneurins, where TCAPs 1 and 3 are independently transcribed as soluble peptides, and TCAPs 2 and 4 remain tethered to their teneurin proprotein. Synthetic TCAP-1 interacts with LPHN, with an association with β-dystroglycan, to induce a tissue-dependent signal cascade to modulate cytoskeletal dynamics. TCAP-1 reduces stress-induced behaviors associated with anxiety, addiction and depression in a variety of models, in part, by regulating synaptic plasticity. Therefore, the TCAP-1-teneurin-LPHN interaction represents a novel receptor-ligand model and may represent a key mechanism underlying the association of behavior and neurological conditions.

Characterization of the teneurin C-terminal associated peptide (TCAP) in the vase tunicate, Ciona intestinalis: A novel peptide system associated with energy metabolism and reproduction

The vase tunicate, Ciona intestinalis, is a protochordate and is considered a sister lineage to the chordates. The recent sequencing of its genome has made this species a particularly important model to understand the genetic basis of vertebrate evolution. However, C. intestinalis is also a highly invasive species along the Atlantic coast of North America and other regions of the world which have caused considerable economic stress due to its biofouling actions and, in particular, negative impacts on the mussel- and oyster-based aquaculture industry. Despite this background, little is known about C. intestinalis physiology. The teneurin C-terminal associated peptides (TCAP) are a family of highly conserved peptide hormones found in most metazoans. Moreover, these peptides have been implicated in the inhibition of stress and stimulation of feeding-based metabolism. We have, therefore, identified this peptide using an in silico approach and characterized its immunological expression in tissues using a mouse polyclonal antiserum. These data indicate that its primary structure is more similar to invertebrate TCAPs relative to vertebrate TCAPs. Immunological expression indicates that it is highly expressed in the digestive tract and gonads consistent with findings in vertebrates. Synthetic mouse TCAP-1 administered into the brachial basket significantly increases the incidence of non-stress contractile behaviors. These findings support the hypothesis that TCAP is a bioactive peptide in C. intestinalis. Thus, C. intestinalis and tunicates in general may offer a simple model to investigate peptide interaction while providing information on how to control this invasive species.