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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 6 of 6. This is the beginning of the thread.
Posted by Netch on April 25, 2010, at 0:24:59
Spadin, a Sortilin-Derived Peptide, Targeting Rodent TREK-1 Channels: A New Concept in the Antidepressant Drug Design
Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.
Posted by markwell on April 25, 2010, at 0:24:59
In reply to Spadin - Antidepressant peptide targets TREK-1, posted by Netch on April 20, 2010, at 8:53:53
Is this ad currently available or in development? Sounds hopeful.
Posted by Netch on April 25, 2010, at 0:25:00
In reply to Re: Spadin - Antidepressant peptide targets TREK-1, posted by markwell on April 20, 2010, at 9:06:35
> Is this ad currently available or in development? Sounds hopeful.
So far only available to laboratory rats. But research for effective TREK1-inhibitors have escalated since it was discovered that TREK1 knockout mice are depression resistant.
http://www.ncbi.nlm.nih.gov/pubmed/16906152?dopt=AbstractPlus
Posted by Phillipa on April 25, 2010, at 0:25:00
In reply to Re: Spadin - Antidepressant peptide targets TREK-1 » markwell, posted by Netch on April 20, 2010, at 9:22:57
Nech this is above my head. So no human has taken it? Phillipa ps so really it doesn't exist right?
Posted by linkadge on April 25, 2010, at 0:25:00
In reply to Re: Spadin - Antidepressant peptide targets TREK-1 » markwell, posted by Netch on April 20, 2010, at 9:22:57
Caffeine inhibits TREK-1 as does the herbal antidepressant tuermeric. Some of the SSRI's have affinity for TREK-1 such as fluoxetine and sertraline. Lamotrigine also has some affinity for TREK-1.
Linkadge
Posted by desolationrower on April 25, 2010, at 0:25:00
In reply to Spadin - Antidepressant peptide targets TREK-1, posted by Netch on April 20, 2010, at 8:53:53
TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK-1 gene, we now show that TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1-/- mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1 / mice, disappears in Trek1-/- mice indicating a central role of TREK-1 in this process. Trek1-/- mice are also resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology.
Keywords:epilepsy, ischemia, neuroprotection, 2P domain K channel, volatile anesthetics
Introduction
INTRODUCTION
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Two-pore-domain potassium channels (K2P channels) form a novel class of K channels identified in various types of neurons (Kim et al, 1995; Wei et al, 1996; Lesage and Lazdunski, 2000; Talley et al, 2003). They are open at membrane potentials across the physiological range and are therefore likely to contribute to the background or leak currents that help set the resting membrane potential and oppose depolarizing influences. They are key components in shaping the characteristics of neuronal excitability. TREK-1 (Fink et al, 1996) is expressed throughout the central nervous system (Fink et al, 1996; Lauritzen et al, 2000; Maingret et al, 2000b; Hervieu et al, 2001; Talley et al, 2001) and is an important member of this family. It is the probable mammalian homolog of the Aplysia S-type K channel (Siegelbaum et al, 1982; Patel et al, 1998), a channel involved in simple forms of learning and memory. TREK-1 is activated by membrane stretch and intracellular acidification (Patel et al, 1998; Maingret et al, 1999b). TREK-1 is opened by arachidonic acid and other polyunsaturated fatty acids (PUFAs) as well as lysophospholipids (LPLs) (Patel et al, 1998; Maingret et al, 2000b). On the other hand, PUFAs and LPLs are potent protective agents against forebrain ischemia and seizures, and it has been proposed that this effect results, at least in part, from their action on TREK channels (Lauritzen et al, 2000; Blondeau et al, 2001, 2002). TREK-1 probably has a central role in the control of excitability by a variety of neurotransmitters. TREK-1 is potently inhibited by neurotransmitters that produce an increase in intracellular cAMP (Patel et al, 1998) and also by those that activate the Gq protein pathway (Lesage et al, 2000; Chemin et al, 2003). The inhibition of TREK channels by glutamate via the activation of group I Gq-coupled metabotropic glutamate receptors requires PTX-insensitive G proteins coupled to phospholipase C (Chemin et al, 2003). TREK-1 is also activated by volatile anesthetics and suggested to be a target in the action of these drugs (Patel et al, 1999). This paper definitively shows that TREK-1 plays a major role in the PUFAs/LPLs-induced neuroprotection against epilepsy and ischemia and that TREK-1-deficient mice display resistance to anesthesia.******************
Antipsychotics inhibit TREK but not TRAAK channels
Susanne Thümmlera, Fabrice Duprata and Michel Lazdunski, a,
aInstitut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Université de Nice-Sophia Antipolis, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France
Received 27 December 2006. Available online 3 January 2007.
Abstract
Schizophrenia is a chronic mental illness affecting 0.4% of the population. Existing antipsychotic drugs are mainly used to treat positive symptoms such as hallucinations but have only poor effects on negative symptoms such as cognitive deficits or depression. TREK and TRAAK channels are two P domain background potassium channels activated by polyunsaturated fatty acids and mechanical stress. TREK but not TRAAK channels are regulated by Gs- and Gq-coupled pathways. The inactivation of the TREK-1 but not the TRAAK channel in mice results in a depression-resistant phenotype. In addition, it has been shown that antidepressants such as fluoxetine or paroxetine directly inhibit TREK channel activity. Here we show that different antipsychotic drugs directly inhibit TREK currents with IC50 values of 1 to 20 μM. No effect is seen on TRAAK channel activity. We conclude that TREK channels might be involved in the therapeutic action of antipsychotics or in their secondary effects. Furthermore, TREK channels could play a role in the pathophysiology of psychiatric disorders such as depression and schizophrenia.*****
Polyunsaturated Fatty Acids Are Cerebral Vasodilators via the TREK-1 Potassium Channel
Nicolas Blondeau ; Olivier Pétrault ; Stella Manta ; Valérie Giordanengo ; Pierre Gounon ; Régis Bordet ; Michel Lazdunski ; and Catherine Heurteaux *
From the Institut de Pharmacologie Moléculaire et Cellulaire (N.B., O.P., S.M., V.G., M.L., C.H.), UMR6097, CNRS Université de Nice Sophia Antipolis, Institut Paul Hamel, Valbonne; Centre Commun de Microscopie Appliquée (P.G.), Université de Nice - Sophia Antipolis; Département de Pharmacologie Médicale (R.B.), EA 1046, Institut de Médecine Prédictive et de Recherche Thérapeutique (IMPRT), Faculté de Médecine de lUniversité de Lille 2, Centre Hospitalier, Universitaire de Lille, Lille Cedex, France.
* To whom correspondence should be addressed. E-mail: heurteaux@ipmc.cnrs.fr.Vessel occlusion is the most frequent cause for impairment of local blood flow within the brain resulting in neuronal damage and is a leading cause of disability and death worldwide. Polyunsaturated fatty acids and especially -linolenic acid improve brain resistance against cerebral ischemia. The purpose of the present study was to evaluate the effects of polyunsaturated fatty acids and particularly -linolenic acid on the cerebral blood flow and on the tone of vessels that regulate brain perfusion. -Linolenic acid injections increased cerebral blood flow and induced vasodilation of the basilar artery but not of the carotid artery. The saturated fatty acid palmitic acid did not produce vasodilation. This suggested that the target of the polyunsaturated fatty acids effect was the TREK-1 potassium channel. We demonstrate the presence of this channel in basilar but not in carotid arteries. We show that vasodilations induced by the polyunsaturated fatty acid in the basilar artery as well as the laser-Doppler flow increase are abolished in TREK-1-/- mice. Altogether these data indicate that TREK-1 activation elicits a robust dilation that probably accounts for the increase of cerebral blood flow induced by polyunsaturated fatty acids such as -linolenic acid or docosahexanoic acid. They suggest that the selective expression and activation of TREK-1 in brain collaterals could play a significant role in the protective mechanisms of polyunsaturated fatty acids against stroke by providing residual circulation during ischemia.
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Mood Stabilizers Activate TREK-1, but not TREK-2
EJ Kim, JY Park, SH Hong, D Kang, J - Biophysical Journal, 2010 - adsabs.harvard.edu
Title: Mood Stabilizers Activate TREK-1, but not TREK-2. Authors: Kim, Eun-Jin; Park, Jae-Yong;
Hong, Seong-Hong; Kang, Dawon; Han, Jaehee. Publication: Biophysical Journal, vol. 98, issue
3, pp. 538a-538a. Publication Date: 01/2010. Origin: CROSSREFwtf would you not write an abstract??
******************
Variation in TREK1 Gene Linked to Depression-
Resistant Phenotype is Associated with Potentiated
Neural Responses to Rewards in HumansAbstract: The TREK1 gene has been linked to a depression-resistant phenotype in rodents and
antidepressant response in humans, but the neural mechanisms underlying these links are unclear.
Because TREK1 is expressed in reward-related basal ganglia regions, it has been hypothesized that
TREK1 genetic variation may be associated with anhedonic symptoms of depression. To investigate
whether TREK1 genetic variation influences reward processing, we genotyped healthy individuals
(n ¼ 31) who completed a monetary incentive delay task during functional magnetic resonance
imaging (fMRI). Three genotypes previously linked to positive antidepressant response were associated
with potentiated basal ganglia activity to gains, but did not influence responses to penalties or
no change feedback. TREK1 genetic variations did not affect basal ganglia volume, and fMRI group
differences were confirmed when accounting for self-report measures of anhedonia. In addition, the
total number of protective TREK1 alleles was associated with stronger responses to gains in
several other reward-related regions, including the dorsal anterior cingulate cortex, orbitofrontal
cortex, and mesial prefrontal cortex. In control analyses, associations between basal ganglia responses
to gains and functional polymorphisms in the dopamine transporter (DAT1) and catechol-O-methyltransferase
(COMT) genes were also explored. Results revealed that TREK1 and DAT/COMT
genotypes were independently related to basal ganglia responses to gains. These findings indicate
that TREK1 genotypes are associated with individual differences in reward-related brain activity.
Future studies in depressed samples should evaluate whether variation in neural responses to
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