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  • Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. 23188715

    Seizures are the manifestation of highly synchronized burst firing of a large population of cortical neurons. Epileptiform bursts with an underlying plateau potential in neurons are a cellular correlate of seizures. Emerging evidence suggests that the plateau potential is mediated by neuronal canonical transient receptor potential (TRPC) channels composed of members of the TRPC1/4/5 subgroup. We previously showed that TRPC1/4 double-knockout (DKO) mice lack epileptiform bursting in lateral septal neurons and exhibit reduced seizure-induced neuronal cell death, but surprisingly have unaltered pilocarpine-induced seizures. Here, we report that TRPC5 knockout (KO) mice exhibit both significantly reduced seizures and minimal seizure-induced neuronal cell death in the hippocampus. Interestingly, epileptiform bursting induced by agonists for metabotropic glutamate receptors in the hippocampal CA1 area is unaltered in TRPC5 KO mice, but is abolished in TRPC1 KO and TRPC1/4 DKO mice. In contrast, long-term potentiation is greatly reduced in TRPC5 KO mice, but is normal in TRPC1 KO and TRPC1/4 DKO mice. The distinct changes from these knockouts suggest that TRPC5 and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Furthermore, the reduced seizure and excitotoxicity and normal spatial learning exhibited in TRPC5 KO mice suggest that TRPC5 is a promising novel molecular target for new therapy.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Transient Receptor Potential Vanilloid 2 Regulates Myocardial Response to Exercise. 26356305

    The myocardial response to exercise is an adaptive mechanism that permits the heart to maintain cardiac output via improved cardiac function and development of hypertrophy. There are many overlapping mechanisms via which this occurs with calcium handling being a crucial component of this process. Our laboratory has previously found that the stretch sensitive TRPV2 channels are active regulators of calcium handling and cardiac function under baseline conditions based on our observations that TRPV2-KO mice have impaired cardiac function at baseline. The focus of this study was to determine the cardiac function of TRPV2-KO mice under exercise conditions. We measured skeletal muscle at baseline in WT and TRPV2-KO mice and subjected them to various exercise protocols and measured the cardiac response using echocardiography and molecular markers. Our results demonstrate that the TRPV2-KO mouse did not tolerate forced exercise although they became increasingly exercise tolerant with voluntary exercise. This occurs as the cardiac function deteriorates further with exercise. Thus, our conclusion is that TRPV2-KO mice have impaired cardiac functional response to exercise.
    Document Type:
    Reference
    Product Catalog Number:
    AB5398
    Product Catalog Name:
    Anti-Vanilloid Receptor Like Protein 1 Antibody, pain, CT

  • Canonical transient receptor potential 3 channels regulate mitochondrial calcium uptake. 23776229

    Mitochondrial Ca(2+) homeostasis is fundamental to regulation of mitochondrial membrane potential, ATP production, and cellular Ca(2+) homeostasis. It has been known for decades that isolated mitochondria can take up Ca(2+) from the extramitochondrial solution, but the molecular identity of the Ca(2+) channels involved in this action is largely unknown. Here, we show that a fraction of canonical transient receptor potential 3 (TRPC3) channels is localized to mitochondria, a significant fraction of mitochondrial Ca(2+) uptake that relies on extramitochondrial Ca(2+) concentration is TRPC3-dependent, and the up- and down-regulation of TRPC3 expression in the cell influences the mitochondrial membrane potential. Our findings suggest that TRPC3 channels contribute to mitochondrial Ca(2+) uptake. We anticipate our observations may provide insights into the mechanisms of mitochondrial Ca(2+) uptake and advance understanding of the physiological role of TRPC3.
    Document Type:
    Reference
    Product Catalog Number:
    MABN748
    Product Catalog Name:
    Anti-TrpC3, clone 10H6 Antibody

  • Central connectivity of transient receptor potential melastatin 8-expressing axons in the brain stem and spinal dorsal horn. 24710558

    Transient receptor potential melastatin 8 (TRPM8) ion channels mediate the detection of noxious and innocuous cold and are expressed by primary sensory neurons, but little is known about the processing of the TRPM8-mediated cold information within the trigeminal sensory nuclei (TSN) and the spinal dorsal horn (DH). To address this issue, we characterized TRPM8-positive (+) neurons in the trigeminal ganglion and investigated the distribution of TRPM8+ axons and terminals, and their synaptic organization in the TSN and in the DH using light and electron microscopic immunohistochemistry in transgenic mice expressing a genetically encoded axonal tracer in TRPM8+ neurons. TRPM8 was expressed in a fraction of small myelinated primary afferent fibers (23.7%) and unmyelinated fibers (76.3%), suggesting that TRPM8-mediated cold is conveyed via C and Aδ afferents. TRPM8+ axons were observed in all TSN, but at different densities in the dorsal and ventral areas of the rostral TSN, which dominantly receive sensory afferents from intra- and peri-oral structures and from the face, respectively. While synaptic boutons arising from Aδ and non-peptidergic C afferents usually receive many axoaxonic contacts and form complex synaptic arrangements, TRPM8+ boutons arising from afferents of the same classes of fibers showed a unique synaptic connectivity; simple synapses with one or two dendrites and sparse axoaxonic contacts. These findings suggest that TRPM8-mediated cold is conveyed via a specific subset of C and Aδ afferent neurons and is processed in a unique manner and differently in the TSN and DH.
    Document Type:
    Reference
    Product Catalog Number:
    AB5896
    Product Catalog Name:
    Anti-P2X3 Receptor Antibody, pain

  • Oligomeric state of purified transient receptor potential melastatin-1 (TRPM1), a protein essential for dim light vision. 25112866

    Transient receptor potential melastatin-1 (TRPM1) is essential for the light-induced depolarization of retinal ON bipolar cells. TRPM1 likely forms a multimeric channel complex, although almost nothing is known about the structure or subunit composition of channels formed by TRPM1 or any of its close relatives. Recombinant TRPM1 was robustly expressed in insect cells, but only a small fraction was localized to the plasma membrane. Similar intracellular localization was observed when TRPM1 was heterologously expressed in mammalian cells. TRPM1 was affinity-purified from Sf9 cells and complexed with amphipol, followed by detergent removal. In blue native gels and size exclusion chromatography, TRPM1 migrated with a mobility consistent with detergent- or amphipol-bound dimers. Cross-linking experiments were also consistent with a dimeric subunit stoichiometry, and cryoelectron microscopy and single particle analysis without symmetry imposition yielded a model with approximate 2-fold symmetrical features. Finally, electron microscopy of TRPM1-antibody complexes revealed a large particle that can accommodate TRPM1 and two antibody molecules. Taken together, these data indicate that purified TRPM1 is mostly dimeric. The three-dimensional structure of TRPM1 dimers is characterized by a small putative transmembrane domain and a larger domain with a hollow cavity. Blue native gels of solubilized mouse retina indicate that TRPM1 is present in two distinct complexes: one similar in size to the recombinant protein and one much larger. Because dimers are likely not functional ion channels, these results suggest that additional partner subunits participate in forming the transduction channel required for dim light vision and the ON pathway.
    Document Type:
    Reference
    Product Catalog Number:
    MAB3073
    Product Catalog Name:
    Anti-G Protein Goα Antibody, clone 2A

  • Brain-derived neurotrophic factor activation of CaM-kinase kinase via transient receptor potential canonical channels induces the translation and synaptic incorporation o ... 22699894

    Glutamatergic synapses in early postnatal development transiently express calcium-permeable AMPA receptors (CP-AMPARs). Although these GluA2-lacking receptors are essential and are elevated in response to brain-derived neurotrophic factor (BDNF), little is known regarding molecular mechanisms that govern their expression and synaptic insertion. Here we show that BDNF-induced GluA1 translation in rat primary hippocampal neurons requires the activation of mammalian target of rapamycin (mTOR) via calcium calmodulin-dependent protein kinase kinase (CaMKK). Specifically, BDNF-mediated phosphorylation of threonine 308 (T308) in AKT, a known substrate of CaMKK and an upstream activator of mTOR-dependent translation, was prevented by (1) pharmacological inhibition of CaMKK with STO-609, (2) overexpression of a dominant-negative CaMKK, or (3) short hairpin-mediated knockdown of CaMKK. GluA1 surface expression induced by BDNF, as assessed by immunocytochemistry using an extracellular N-terminal GluA1 antibody or by surface biotinylation, was impaired following knockdown of CaMKK or treatment with STO-609. Activation of CaMKK by BDNF requires transient receptor potential canonical (TRPC) channels as SKF-96365, but not the NMDA receptor antagonist d-APV, prevented BDNF-induced GluA1 surface expression as well as phosphorylation of CaMKI, AKT(T308), and mTOR. Using siRNA we confirmed the involvement of TRPC5 and TRPC6 subunits in BDNF-induced AKT(T308) phosphorylation. The BDNF-induced increase in mEPSC was blocked by IEM-1460, a selected antagonist of CP-AMPARs, as well as by the specific repression of acute GluA1 translation via siRNA to GluA1 but not GluA2. Together these data support the conclusion that newly synthesized GluA1 subunits, induced by BDNF, are readily incorporated into synapses where they enhance the expression of CP-AMPARs and synaptic strength.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Differential expression of canonical (classical) transient receptor potential channels in guinea pig enteric nervous system. 18925632

    The canonical transient receptor potential (TRPC) family of ion channels is implicated in many neuronal processes including calcium homeostasis, membrane excitability, synaptic transmission, and axon guidance. TRPC channels are postulated to be important in the functional neurobiology of the enteric nervous system (ENS); nevertheless, details for expression in the ENS are lacking. Reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry were used to study the expression and localization of TRPC channels. We found mRNA transcripts, protein on Western blots, and immunoreactivity (IR) for TRPC1/3/4/6 expressed in the small intestinal ENS of adult guinea pigs. TRPC1/3/4/6-IR was localized to distinct subpopulations of enteric neurons and was differentially distributed between the myenteric and submucosal divisions of the ENS. TRPC1-IR was widely distributed and localized to neurons with cholinergic, calretinin, and nitrergic neuronal immunochemical codes in the myenteric plexus. It was localized to both cholinergic and noncholinergic secretomotor neurons in the submucosal plexus. TRPC3-IR was found only in the submucosal plexus and was expressed exclusively by neuropeptide Y-IR neurons. TRPC4/6-IR was expressed in only a small population of myenteric neurons, but was abundantly expressed in the submucosal plexus. TRPC4/6-IR was coexpressed with both cholinergic and nitrergic neurochemical codes in the myenteric plexus. In the submucosal plexus, TRPC4/6-IR was expressed exclusively in noncholinergic secretomotor neurons. No TRPC1/3/4/6-IR was found in calbindin-IR neurons. TRPC3/4/6-IR was widely expressed along varicose nerve fibers and colocalized with synaptophysin-IR at putative neurotransmitter release sites. Our results suggest important roles for TRPC channels in ENS physiology and neuronal regulation of gut function.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Angiotensin II induces membrane trafficking of natively expressed transient receptor potential vanilloid type 4 channels in hypothalamic 4B cells. 25080500

    Transient receptor potential vanilloid family type 4 (TRPV4) channels are expressed in central neuroendocrine neurons and have been shown to be polymodal in other systems. We previously reported that in the rodent, a model of dilutional hyponatremia associated with hepatic cirrhosis, TRPV4 expression is increased in lipid rafts from the hypothalamus and that this effect may be angiotensin dependent. In this study, we utilized the immortalized neuroendocrine rat hypothalamic 4B cell line to more directly test the effects of angiotensin II (ANG II) on TRPV4 expression and function. Our results demonstrate the expression of corticotropin-releasing factor (CRF) transcripts, for sex-determining region Y (SRY) (male genotype), arginine vasopressin (AVP), TRPV4, and ANG II type 1a and 1b receptor in 4B cells. After a 1-h incubation in ANG II (100 nM), 4B cells showed increased TRPV4 abundance in the plasma membrane fraction, and this effect was prevented by the ANG II type 1 receptor antagonist losartan (1 μM) and by a Src kinase inhibitor PP2 (10 μM). Ratiometric calcium imaging experiments demonstrated that ANG II incubation potentiated TRPV4 agonist (GSK 1016790A, 20 nM)-induced calcium influx (control 18.4 ± 2.8% n = 5 and ANG II 80.5 ± 2.4% n = 5). This ANG II-induced increase in calcium influx was also blocked by 1 μM losartan and 10 μM PP2 (losartan 26.4 ± 3.8% n = 5 and PP2 19.7 ± 3.9% n = 5). Our data suggests that ANG II can increase TRPV4 channel membrane expression in 4B cells through its action on AT1R involving a Src kinase pathway.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Pdx-1 activates islet α- and β-cell proliferation via a mechanism regulated by transient receptor potential cation channels 3 and 6 and extracellular signal-regulated kin ... 23938296

    The homeodomain transcription factor Pdx-1 has important roles in pancreatic development and β-cell function and survival. In the present study, we demonstrate that adenovirus-mediated overexpression of Pdx-1 in rat or human islets also stimulates cell replication. Moreover, cooverexpression of Pdx-1 with another homeodomain transcription factor, Nkx6.1, has an additive effect on proliferation compared to either factor alone, implying discrete activating mechanisms. Consistent with this, Nkx6.1 stimulates mainly β-cell proliferation, whereas Pdx-1 stimulates both α- and β-cell proliferation. Furthermore, cyclins D1/D2 are upregulated by Pdx-1 but not by Nkx6.1, and inhibition of cdk4 blocks Pdx-1-stimulated but not Nkx6.1-stimulated islet cell proliferation. Genes regulated by Pdx-1 but not Nkx6.1 were identified by microarray analysis. Two members of the transient receptor potential cation (TRPC) channel family, TRPC3 and TRPC6, are upregulated by Pdx-1 overexpression, and small interfering RNA (siRNA)-mediated knockdown of TRPC3/6 or TRPC6 alone inhibits Pdx-1-induced but not Nkx6.1-induced islet cell proliferation. Pdx-1 also stimulates extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, an effect partially blocked by knockdown of TRPC3/6, and blockade of ERK1/2 activation with a MEK1/2 inhibitor partially impairs Pdx-1-stimulated proliferation. These studies define a pathway by which overexpression of Pdx-1 activates islet cell proliferation that is distinct from and additive to a pathway activated by Nkx6.1.
    Document Type:
    Reference
    Product Catalog Number:
    05-797R
    Product Catalog Name:
    Anti-phospho-Erk1/2 (Thr202/Tyr204, Thr185/Tyr187)Antibody, recombinant clone AW39R, rabbit monoclonal

  • Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors. 16513770

    A recent study has demonstrated that increasing the intrathoracic temperature from 36 degrees C to 41 degrees C induced a distinct stimulatory and sensitizing effect on vagal pulmonary C-fiber afferents in anesthetized rats (J Physiol 565: 295-308, 2005). We postulated that these responses are mediated through a direct activation of the temperature-sensitive transient receptor potential vanilloid (TRPV) receptors by hyperthermia. To test this hypothesis, we studied the effect of increasing temperature on pulmonary sensory neurons that were isolated from adult rat nodose/jugular ganglion and identified by retrograde labeling, using the whole cell perforated patch-clamping technique. Our results showed that increasing temperature from 23 degrees C (or 35 degrees C) to 41 degrees C in a ramp pattern evoked an inward current, which began to emerge after exceeding a threshold of approximately 34.4 degrees C and then increased sharply in amplitude as the temperature was further increased, reaching a peak current of 173 +/- 27 pA (n = 75) at 41 degrees C. The temperature coefficient, Q10, was 29.5 +/- 6.4 over the range of 35-41 degrees C. The peak inward current was only partially blocked by pretreatment with capsazepine (Delta I = 48.1 +/- 4.7%, n = 11) or AMG 9810 (Delta I = 59.2 +/- 7.8%, n = 8), selective antagonists of the TRPV1 channel, but almost completely abolished (Delta I = 96.3 +/- 2.3%) by ruthenium red, an effective blocker of TRPV1-4 channels. Furthermore, positive expressions of TRPV1-4 transcripts and proteins in these neurons were demonstrated by RT-PCR and immunohistochemistry experiments, respectively. On the basis of these results, we conclude that increasing temperature within the normal physiological range can exert a direct stimulatory effect on pulmonary sensory neurons, and this effect is mediated through the activation of TRPV1, as well as other subtypes of TRPV channels.
    Document Type:
    Reference
    Product Catalog Number:
    AB5398
    Product Catalog Name:
    Anti-Vanilloid Receptor Like Protein 1 Antibody, pain, CT