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December 2011

I created a new, fully updated page for TAAR1 — Preceding unsigned comment added by Stevereichh (talk • contribs) 01:39, 3 December 2011 (UTC)[reply]

Firing rate

I recently read this article http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618978/ which talks about the role of TAAR1 in reducing the firing rate of the cell (at least for dopaminergic cells?). I hope someone has the time to give this topic some proper description (oddly the caption on the image near the bottom of the page mentions this briefly). I have my own hypotheses that TAAR1 may be a neuroprotective receptor, reducing the firing rate to stop more calcium from flowing into the cell, and reversing the flow of dopamine through the DAT to reduce oxidative stress in the cytoplasm. But this may be putting the cart before the horse. — Preceding unsigned comment added by 96.21.96.70 (talk) 17:48, 6 March 2014 (UTC)[reply]

I've updated the page from amphetamine's pharmacodynamics section. Seppi333 (Insert 2¢ | Maintained) 01:33, 7 March 2014 (UTC)[reply]

Content/Reviews to add

PMID 18473983 —

In progress

PMID 17888514 —

In progress

PMID 21073468 —

Partly done

Seppi333 (Insert 2¢ | Maintained) 22:11, 14 March 2014 (UTC)[reply]

Updated TAAR1 pharmacology + TAAR1 receptor interactions: DRD2, A2a, NMDAR

Worth adding in Amphetamine#Pharmacodynamics/TAAR1 and elsewhere.

TAAR1 pharmacology review published last month^[1] Added

Should probably add a sentence on TAAR1-adrenoceptor-A2a^[2] ( Added) and TAAR1-DRD2 heteromers and their function/significance in Amphetamine#Pharmacodynamics for completeness

For TAAR1, PEA+other TAs, and isoprenaline - PEA+Isop pharmacodynamics update^[3]

—Seppi333 (Insert 2¢) 04:58, 13 July 2015 (UTC)[reply]

References

^ Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2015.06.026. PMID 26093041.
It is important to note that in addition to the brain, TAAR1 is also expressed in the spinal cord (Gozal et al., 2014) and periphery (Revel et al., 2012c). It has been shown that TAAR1 is expressed and regulates immune function in rhesus monkey leukocytes (Babusyte et al., 2013; Nelson et al., 2007; Panas et al., 2012). In granulocytes, TAAR1 is necessary for chemotaxic migration of cells towards TAAR1 agonists. In addition, TAAR1 signaling in B and T cells can trigger immunoglobulin and cytokine release, respectively (Babusyte et al., 2013). TAAR1 is also expressed in the islets of Langerhans, stomach and intestines based on LacZ staining patterns carried out on TAAR1-KO LacZ mice (Revel et al., 2012c). Interestingly, the administration of selective TAAR1 partial agonist RO5263397 reverses the side effect of weight gain observed with the antipsychotic olanzapine, indicating that peripheral TAAR1 signalling can regulate metabolic homeostasis (Revel et al., 2012b).

Bradaia et al. discovered that antagonism of TAAR1 in mouse brain slices resulted in increased dopamine D2 receptor agonist potency (Bradaia et al., 2009). Further studies by Espinoza et al., showed formation of heterodimers between the dopamine D2 receptor and TAAR1 in HEK cells and that haloperidol treatment (a D2 dopamine receptor antagonist) enhanced TAAR1 signalling in these cells. Interestingly, TAAR1-KO mouse showed a reduction in haloperidol induced c-fos expression and reduced catalepsy compared to WT littermates (Espinoza et al., 2011) further demonstrating the interaction between D2R and TAAR1 in vivo. ... On the other hand, there is also evidence indicating a role of TAAR1 in modulating the activity of presynaptic D2 dopamine receptors as well. In VTA dopaminergic neurons, stimulation of TAAR1 induces a decrease in D2 receptor activity and promotes D2 receptor desensitization (Bradaia et al., 2009; Revel et al., 2011). Similarly, D2 dopamine autoreceptor functions are also altered in the nucleus accumbens (NAcc) of TAAR1-KO mice (Leo et al., 2014). In fact, fast scan cyclic voltammetry (FSCV) and in vivo microdialysis studies have revealed that in the NAcc but not in the dorsal striatum of TAAR1-KO mice, the basal dopamine release is increased. Conversely, the activation of TAAR1 with selective agonists decreases DA release in WT mice. Finally, using FSCV it was possible to directly demonstrate that D2 dopamine autoreceptor activity was reduced in TAAR1-KO animals. All these studies reveal an important presynaptic role of TAAR1 in modulating of D2 receptor autoinhibition (Leo et al., 2014).

Studies using the rhesus monkey TAAR1 have shown that this receptor interacts with the monoamine transporters DAT, SERT, and NET in HEK cells (Miller et al., 2005; Xie and Miller, 2007; Xie et al., 2007). It has been hypothesized that TAAR1 interaction with these transporters might provide a mechanism by which TAAR1 ligands can enter the cytoplasm and bind to TAAR1 in intracellular compartments. A recent study has shown that in rat neonatal motor neurons, trace-amine specific signalling requires the presence and function of the transmembrane solute carrier SLC22A but not that of monoamine transporters (DAT, SERT, and NET) (Gozal et al., 2014). Specifically, it was shown that addition of β-PEA, tyramine, or tryptamine induced locomotor like activity (LLA) firing patterns of these neurons in the presence of N-Methyl D-Aspartate. Temporally, it was found that the trace amine induction of LLA is delayed compared to serotonin and norepinephrine induced LLA, indicating the target site for the trace amines is not located on the plasma membrane and could perhaps be intracellular. Importantly, blocking of SLC22A with pentamidine abolished trace amine induced LLA, indicating that trace amine induced LLA does not act on receptors found on the plasma membrane but requires their transport to the cytosol by SLC22A for induction of LLA.

Mechanistically, it was found that TAAR1 modulates the firing rate of dopaminergic neurons through the activation of the kir3 channels through a Gαs specific mechanism. Furthermore, Bradaia et al. reported a functional link between TAAR1 and the dopamine D2 receptors where antagonism of TAAR1 with EPPTB resulted in an increased dopamine D2 receptor agonist potency.

While there is a body of evidence showing that TAAR1 is an intracellular receptor, it does not preclude the fact that TAAR1, if expressed on the plasma membrane, could have a separate function from the receptors located intracellularly ... While the definitive localization of TAAR1 remains unclear, there is evidence indicating that GPCRs can signal in early endosomal compartments (Irannejad et al., 2013) as well as nuclear membranes (Tadevosyan et al., 2012). However, activation of kir3 channels through Gαs protein in dopaminergic neurons by TAAR1 is most likely occurring at the plasma membrane (Revel et al., 2011) and therefore it is possible that TAAR1 could function both in intracellular compartments as well as the plasma membrane.

Several lines of evidence suggest that TA levels, specifically β-PEA, correlate with depression. Indeed, decreased levels of β-PEA have been detected in CSF of depressed patients compared to controls (Sandler et al., 1979) and β-PEA or L-phenylalanine (precursor of β- PEA) supplementation in these patients produced relief from depression (Sabelli et al., 1996). In addition, MAO inhibitors are effective treatments for atypical depression (Jarrett et al., 1999) where inhibition of MAO is known to increase systemic levels of TAs (Murphy et al., 1998). In fact, an increase in β-PEA levels has been observed in the MAO-B knockout mouse (Grimsby et al., 1997).

More recently, a role of TAAR1 in modulating prefrontal cortex processes has also been reported (Espinoza et al., 2015b). ... In agreement with this expression pattern, it was shown that in TAAR1-KO mice there is a deficient functionality of NMDA-mediated current of layer V pyramidal neurons and an altered subunit composition of NMDA receptors. Behaviorally, TAAR1-KO mice presented aberrant cognitive behaviors, indicating an impulsive and perseverative phenotype. These data indicate that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and in certain aspects of cognition.

Interestingly, both the full and the partial agonist, RO5166017 and RO5203648, were able to decrease impulsivity, a distinct behavior involved in the pathophysiology of several brain pathologies including ADHD and drug addiction (Espinoza et al., 2015b).
{{cite journal}}: line feed character in |quote= at position 7 (help)
^ Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, Hoefig CS, Müller A, Köhrle J, Grüters A, Krude H, Mittag J, Schöneberg T, Kleinau G, Biebermann H (June 2015). "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling". J. Mol. Endocrinol. 54 (3): 205–216. doi:10.1530/JME-15-0003. PMID 25878061. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.
^ Kleinau G, Pratzka J, Nürnberg D, Grüters A, Führer-Sakel D, Krude H, Köhrle J, Schöneberg T, Biebermann H (October 2011). "Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists". PLoS ONE. 6 (10): e27073. doi:10.1371/journal.pone.0027073. PMC 3205048. PMID 22073124.{{cite journal}}: CS1 maint: unflagged free DOI (link)
"Table 1: EC₅₀ values of different agonists at hTAAR1, hADRB1 and hADRB2."

Lots of error messages

@Boghog: I just noticed there's a lot of error messages showing up in the refs section. I noticed you recently adjusted the ref structure on the page, so I wasn't sure how you wanted to handle this, but it appears most of the errors involve the list-defined refs. Seppi333 (Insert 2¢) 22:37, 8 October 2015 (UTC)[reply]

Sorry, I didn't complete the job leaving behind duplicate citation templates. The duplicates have now been been removed. Boghog (talk) 06:18, 9 October 2015 (UTC)[reply]

No worries.

ty. Seppi333 (Insert 2¢) 15:17, 9 October 2015 (UTC)[reply]

New TAAR1 review by Miller+Grandy

^[1] Added

References

^ Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139.

- update for this page, amph, meth, trace amine, addiction. Seppi333 (Insert 2¢) 22:28, 28 January 2016 (UTC)[reply]

Another new review to add

^[1]

References

^ Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomed. Pharmacother. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID 27424325.

Other papers to consider as citations for new content:
- PMID 28123023 (Jan 2017) Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior.
- PMID 28069535 (Jan 2017) Thyronamines and Analogues - The Route from Rediscovery to Translational Research on Thyronergic Amines.
- PMID 27823885 (Oct 2016) Novel biguanide-based derivatives scouted as TAAR1 agonists: Synthesis, biological evaluation, ADME prediction and molecular docking studies.

Seppi333 (Insert 2¢) 18:35, 29 January 2017 (UTC)[reply]

Lead

I'm not sure what the issue with the current lead is, but deleting the vast majority of the lead isn't the correct way to address an issue with a statement. Seppi333 (Insert 2¢) 22:10, 5 November 2017 (UTC)[reply]

@Danlsaur 94: I'm open to revising the lead of this article; but, if we're going to delete statements that are cited by references, I'd need you to indicate what statements are of concern and why you think they need to be revised. Seppi333 (Insert 2¢) 22:50, 5 November 2017 (UTC)[reply]

[TAAR1_2015_in-vivo_pharmacology_excerpts-1] Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (June 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur. J. Pharmacol. doi:10.1016/j.ejphar.2015.06.026. PMID 26093041.
It is important to note that in addition to the brain, TAAR1 is also expressed in the spinal cord (Gozal et al., 2014) and periphery (Revel et al., 2012c). It has been shown that TAAR1 is expressed and regulates immune function in rhesus monkey leukocytes (Babusyte et al., 2013; Nelson et al., 2007; Panas et al., 2012). In granulocytes, TAAR1 is necessary for chemotaxic migration of cells towards TAAR1 agonists. In addition, TAAR1 signaling in B and T cells can trigger immunoglobulin and cytokine release, respectively (Babusyte et al., 2013). TAAR1 is also expressed in the islets of Langerhans, stomach and intestines based on LacZ staining patterns carried out on TAAR1-KO LacZ mice (Revel et al., 2012c). Interestingly, the administration of selective TAAR1 partial agonist RO5263397 reverses the side effect of weight gain observed with the antipsychotic olanzapine, indicating that peripheral TAAR1 signalling can regulate metabolic homeostasis (Revel et al., 2012b).

Bradaia et al. discovered that antagonism of TAAR1 in mouse brain slices resulted in increased dopamine D2 receptor agonist potency (Bradaia et al., 2009). Further studies by Espinoza et al., showed formation of heterodimers between the dopamine D2 receptor and TAAR1 in HEK cells and that haloperidol treatment (a D2 dopamine receptor antagonist) enhanced TAAR1 signalling in these cells. Interestingly, TAAR1-KO mouse showed a reduction in haloperidol induced c-fos expression and reduced catalepsy compared to WT littermates (Espinoza et al., 2011) further demonstrating the interaction between D2R and TAAR1 in vivo. ... On the other hand, there is also evidence indicating a role of TAAR1 in modulating the activity of presynaptic D2 dopamine receptors as well. In VTA dopaminergic neurons, stimulation of TAAR1 induces a decrease in D2 receptor activity and promotes D2 receptor desensitization (Bradaia et al., 2009; Revel et al., 2011). Similarly, D2 dopamine autoreceptor functions are also altered in the nucleus accumbens (NAcc) of TAAR1-KO mice (Leo et al., 2014). In fact, fast scan cyclic voltammetry (FSCV) and in vivo microdialysis studies have revealed that in the NAcc but not in the dorsal striatum of TAAR1-KO mice, the basal dopamine release is increased. Conversely, the activation of TAAR1 with selective agonists decreases DA release in WT mice. Finally, using FSCV it was possible to directly demonstrate that D2 dopamine autoreceptor activity was reduced in TAAR1-KO animals. All these studies reveal an important presynaptic role of TAAR1 in modulating of D2 receptor autoinhibition (Leo et al., 2014).

Studies using the rhesus monkey TAAR1 have shown that this receptor interacts with the monoamine transporters DAT, SERT, and NET in HEK cells (Miller et al., 2005; Xie and Miller, 2007; Xie et al., 2007). It has been hypothesized that TAAR1 interaction with these transporters might provide a mechanism by which TAAR1 ligands can enter the cytoplasm and bind to TAAR1 in intracellular compartments. A recent study has shown that in rat neonatal motor neurons, trace-amine specific signalling requires the presence and function of the transmembrane solute carrier SLC22A but not that of monoamine transporters (DAT, SERT, and NET) (Gozal et al., 2014). Specifically, it was shown that addition of β-PEA, tyramine, or tryptamine induced locomotor like activity (LLA) firing patterns of these neurons in the presence of N-Methyl D-Aspartate. Temporally, it was found that the trace amine induction of LLA is delayed compared to serotonin and norepinephrine induced LLA, indicating the target site for the trace amines is not located on the plasma membrane and could perhaps be intracellular. Importantly, blocking of SLC22A with pentamidine abolished trace amine induced LLA, indicating that trace amine induced LLA does not act on receptors found on the plasma membrane but requires their transport to the cytosol by SLC22A for induction of LLA.

Mechanistically, it was found that TAAR1 modulates the firing rate of dopaminergic neurons through the activation of the kir3 channels through a Gαs specific mechanism. Furthermore, Bradaia et al. reported a functional link between TAAR1 and the dopamine D2 receptors where antagonism of TAAR1 with EPPTB resulted in an increased dopamine D2 receptor agonist potency.

While there is a body of evidence showing that TAAR1 is an intracellular receptor, it does not preclude the fact that TAAR1, if expressed on the plasma membrane, could have a separate function from the receptors located intracellularly ... While the definitive localization of TAAR1 remains unclear, there is evidence indicating that GPCRs can signal in early endosomal compartments (Irannejad et al., 2013) as well as nuclear membranes (Tadevosyan et al., 2012). However, activation of kir3 channels through Gαs protein in dopaminergic neurons by TAAR1 is most likely occurring at the plasma membrane (Revel et al., 2011) and therefore it is possible that TAAR1 could function both in intracellular compartments as well as the plasma membrane.

Several lines of evidence suggest that TA levels, specifically β-PEA, correlate with depression. Indeed, decreased levels of β-PEA have been detected in CSF of depressed patients compared to controls (Sandler et al., 1979) and β-PEA or L-phenylalanine (precursor of β- PEA) supplementation in these patients produced relief from depression (Sabelli et al., 1996). In addition, MAO inhibitors are effective treatments for atypical depression (Jarrett et al., 1999) where inhibition of MAO is known to increase systemic levels of TAs (Murphy et al., 1998). In fact, an increase in β-PEA levels has been observed in the MAO-B knockout mouse (Grimsby et al., 1997).

More recently, a role of TAAR1 in modulating prefrontal cortex processes has also been reported (Espinoza et al., 2015b). ... In agreement with this expression pattern, it was shown that in TAAR1-KO mice there is a deficient functionality of NMDA-mediated current of layer V pyramidal neurons and an altered subunit composition of NMDA receptors. Behaviorally, TAAR1-KO mice presented aberrant cognitive behaviors, indicating an impulsive and perseverative phenotype. These data indicate that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and in certain aspects of cognition.

Interestingly, both the full and the partial agonist, RO5166017 and RO5203648, were able to decrease impulsivity, a distinct behavior involved in the pathophysiology of several brain pathologies including ADHD and drug addiction (Espinoza et al., 2015b).
{{cite journal}}: line feed character in |quote= at position 7 (help)

[TAAR1–adrenoceptor_A2a_heteromer-2] Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, Hoefig CS, Müller A, Köhrle J, Grüters A, Krude H, Mittag J, Schöneberg T, Kleinau G, Biebermann H (June 2015). "3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling". J. Mol. Endocrinol. 54 (3): 205–216. doi:10.1530/JME-15-0003. PMID 25878061. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.

[TAAR1_ligands_and_TA_adrenergic_receptor_binding-3] Kleinau G, Pratzka J, Nürnberg D, Grüters A, Führer-Sakel D, Krude H, Köhrle J, Schöneberg T, Biebermann H (October 2011). "Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists". PLoS ONE. 6 (10): e27073. doi:10.1371/journal.pone.0027073. PMC 3205048. PMID 22073124.{{cite journal}}: CS1 maint: unflagged free DOI (link)
"Table 1: EC₅₀ values of different agonists at hTAAR1, hADRB1 and hADRB2."

[Miller+Grandy_2016-4] Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"-The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMID 26644139.

[Human_trace_amines_and_hTAARs_October_2016_review-5] Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomed. Pharmacother. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID 27424325.

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