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. 2017 Aug 16;8:198.
doi: 10.3389/fendo.2017.00198. eCollection 2017.

3-Iodothyronamine, a Novel Endogenous Modulator of Transient Receptor Potential Melastatin 8?

Free PMC article

3-Iodothyronamine, a Novel Endogenous Modulator of Transient Receptor Potential Melastatin 8?

Noushafarin Khajavi et al. Front Endocrinol (Lausanne). .
Free PMC article


The decarboxylated and deiodinated thyroid hormone (TH) derivative, 3-iodothyronamine (3-T1AM), is suggested to be involved in energy metabolism and thermoregulation. G protein-coupled receptors (GPCRs) are known as the main targets for 3-T1AM; however, transient receptor potential channels (TRPs) were also recently identified as new targets of 3-T1AM. This article reviews the current knowledge of a putative novel role of 3-T1AM in the modulation of TRPs. Specifically, the TRP melastatin 8 (TRPM8) was identified as a target of 3-T1AM in different cell types including neoplastic cells, whereby 3-T1AM significantly increased cytosolic Ca2+ through TRPM8 activation. Similarly, the β-adrenergic receptor is involved in 3-T1AM-induced Ca2+ influx. Therefore, it has been suggested that 3-T1AM-induced Ca2+ mobilization might be due to β-adrenergic receptor/TRPM8 channel interaction, which adds to the complexity of GPCR regulation by TRPs. It has been revealed that TRPM8 activation leads to a decline in TRPV1 activity, which may be of therapeutic benefit in clinical circumstances such as treatment of TRPV1-mediated inflammatory hyperalgesia, colitis, and dry eye syndrome. This review also summarizes the inverse association between changes in TRPM8 and TRPV1 activity after 3-T1AM stimulation. This finding prompted further detailed investigations of the interplay between 3-T1AM and the GPCR/TRPM8 axis and indicated the probability of additional GPCR/TRP constellations that are modulated by this TH derivative.

Keywords: 3-iodothyronamine; calcium; inflammation; thermoregulation; transient receptor potential channel.


Figure 1
Figure 1
Suggested Ca2+ signal transduction pathways induced by 3-iodothyronamine (3-T1AM). Two G protein-coupled receptors (GPCRs), known as trace amine-associated receptor 1 (TAAR1) and β-adrenergic receptors, can be activated and one GPCR known as muscarinic type 3 receptor can be suppressed by 3-T1AM. 3-T1AM increases [Ca2+]i via a member of the transient receptor channel superfamily known as transient receptor potential channel melastatin 8 (TRPM8) (menthol or cold receptor), and this effect is blocked by BCTC. 3-T1AM may either directly activate TRPM8 by a GPCR-independent mechanism or indirectly via the β/γ-subunits of Gi/o downstream of β-adrenergic receptors. TRPM8 activation by 3-T1AM inhibits TRPV1 (capsaicin or heat receptor)-induced Ca2+ influx. Notably, 3-T1AM may also directly suppress TRPV1 by a GPCR-independent mechanism (↓[Ca2+]i). So far, the involvement of other GPCRs and TRPs in 3-T1AM-induced signaling effects remained elusive.

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