TRPCing around the hypothalamus

Abstract

All of the canonical transient receptor potential channels (TRPC) with the exception of TRPC 2 are expressed in hypothalamic neurons and are involved in multiple homeostatic functions. Although the metabotropic glutamate receptors have been shown to be coupled to TRPC channel activation in cortical and sub-cortical brain regions, in the hypothalamus multiple amine and peptidergic G protein-coupled receptors (GPCRs) and growth factor/cytokine receptors are linked to activation of TRPC channels that are vital for reproduction, temperature regulation, arousal and energy homeostasis. In addition to the neurotransmitters, circulating hormones like insulin and leptin through their cognate receptors activate TRPC channels in POMC neurons. Many of the post-synaptic effects of the neurotransmitters and hormones are regulated in different physiological states by expression of TRPC channels in the post-synaptic neurons. Therefore, TRPC channels are key targets not only for neurotransmitters but circulating hormones in their vital role to control multiple hypothalamic functions, which is the focus of this review.

Deletion of Stim1 in hypothalamic arcuate nucleus Kiss1 neurons potentiates synchronous GCaMP activity and protects against diet-induced obesity

“…To elucidate the TRPC5 channel contribution to the postsynaptic activity of Kiss1 ARH neurons, we perfused TTX to block fast sodium channels and found that HC 070 significantly suppressed the senktide-induced inward current ( Figure 5E, F and H ). The I/V plot for the senktide-induced cation current exhibited the typical double-rectifying characteristics of TRPC5 channels with a reversal of −10 mV ( Figure 5G ) as we previously reported (Kelly Martin J. et al, 2018). These results indicate that TRPC5 channels also contribute to the synchronous activity of Stim1 kko neurons.…”

“…As expected, the selective PI3K inhibitor wortmannin (100 nM) robustly blocked the potentiation of the slow EPSP by insulin ( Figure 4A-E ). Next, we investigated a downstream effector of PI3K signaling based on our previous findings that TPRC5 channel protein is expressed in Kiss1 ARH neurons ( Figure 1C ) (Qiu J. et al, 2011) and is activated by the NKB agonist senktide (Kelly Martin J. et al, 2018). To measure the TRPC5 channels contribution to the slow EPSP, we used a ratio method in which a slow EPSP was generated with optogenetic stimulation (20 Hz, 10 s) of a Kiss1 Cre :ChR2 neuron and then tested again 10 min later after drug exposure (Qiu J. et al, 2016).…”

“…The metabolic hormones leptin and insulin excite/depolarize Kiss1 ARH , and proopiomelanocortin (POMC), neurons through activation of TRPC5 channels (Kelly Martin J. et al, 2018; Qiu J. et al, 2011; Qiu J. et al, 2010; Qiu J. et al, 2014). In contrast, leptin and insulin inhibit/hyperpolarizes neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons via activation of K ATP channels (Qiu J. et al, 2020; Qiu J., Wagner, et al, 2018; Qiu J. et al, 2014).…”

Arcuate Kisspeptin Neurons Coordinate Reproductive Activities with Metabolism

“…28 NKB binds to TacR3 in neighboring Kiss1 ARH neurons to open TRPC5 channels to cause a robust depolarization (slow EPSP); coreleased dynorphin feeds back to bind to presynaptic κ-opioid receptors to limit the release of NKB to discrete bursts of activity and presumably postsynaptic TacR3 desensitization. 28,53 Thus, high-frequency autoexcitation of Kiss1 ARH neurons ipsilaterally is able to recruit Kiss1 ARH neurons bilaterally, which is dependent on NKB activation of TRPC5 channels to induce synchronization of this critical neural network that underlies the pulse generator activity in mammalian females. 27,28 The pulsatile LH secretion from NKB activation of Kiss1 ARH neurons was first shown in the goat through recording of multiunit activity (MUA) in close proximity of Kiss1 neurons simultaneously with measurements of LH release in the periphery.…”

“…3), which may be important for fertility, given that the TacR3 agonist senktide (and NKB) also excites Kiss1 ARH neurons through TRPC5 channels and NKB and TacR3 are critical for fertility. 53,68 Insulin, like leptin, affects neuropeptide expression in the hypothalamus and food intake. 69 Interestingly, insulin, similar to leptin, depolarizes and increases action potential firing in both POMC and Kiss1 ARH neurons.…”