Prorenin Modulates Intrinsic Excitability of Hypothalamic Tyrosine Hydroxylase Neurons Through SK Channel Activation

In tyrosine hydroxylase (TH)–expressing neurons of the paraventricular nucleus (PVN), (Pro)renin receptor (PRR) signaling plays a role in central regulation of glucose homeostasis. We recently demonstrated that firing of PVNTH neurons is inhibited when PRR is activated by its ligand, prorenin, and that this effect is in turn implicated in high-fat diet (HFD)–induced hyperglycemia. The current work was undertaken to identify cellular mechanism(s) through which PRR signaling inhibits PVNTH neurons. To isolate intrinsic membrane properties and excitability of PVNTH neurons, we performed whole-cell patch-clamp recordings from Th-Cre::tdTomato mice while blocking fast synaptic transmission with antagonists of GABA-A (picrotoxin, 50 μM), AMPA/kainate receptors (CNQX, 5 μM), and NMDA receptors (D-APV, 50 μM). Prorenin (2.5 nM, n = 9 neurons from 6 mice) significantly reduced both the resting membrane potential (RMP; −39.7 ± 1.3 to −41.7 ± 1.0 mV; P < 0.05) and action potential frequency (6.0 ± 1.2 to 4.2 ± 1.0 Hz; P < 0.01) of PVNTH neurons. Prorenin also enhanced the after-hyperpolarization (AHP), increasing both AHP amplitude (6.9 ± 1.4 to 9.2 ± 1.7 mV; P < 0.01) and duration (10.2 ± 2.7 to 12.2 ± 2.9 ms; P < 0.05). Since small-conductance Ca 2 + -activated potassium (SK) channels are major contributors to AHP, we next performed single-nucleus RNA sequencing and immunofluorescence analysis. This work confirmed PVNTH neurons express SK2 and SK3, but not SK1 channels. Using the SK blocker, apamine (100 nM), we confirmed apamin-sensitive SK current in PVNTH neurons (from 2.2 ± 0.5 pA/pF to 0.2 ± 0.1 pA/pF; P< 0.01, n = 6 neurons from 6 mice) and report that apamine blocked the inhibitory effect of prorenin on RMP (−36.8 ± 1.9 mV and −35.9 ± 2.0 mV), firing rate (7.9 ± 2.0 Hz and 7.5 ± 1.7 Hz), and AHP in these neurons (4.0 ± 0.8 mV and 4.3 ± 0.9 mV) (all P > 0.05, prorenin + apamin vs. apamin alone; n = 10 neurons from 8 mice). Voltage-clamp experiments further showed that prorenin increases SK current density (1.2 ± 0.2 to 2.0 ± 0.3 pA/pF; P < 0.05, n = 8 neurons from 5 mice), an effect abolished by inhibition of ERK1/2 (SCH2656157, 2.3 ± 0.2 pA/pF to 2.3 ± 0.2 pA/pF, P >0.05, n = 9 neurons from 7 mice), but not by PI3K signaling (GSK2656157, 1.2 ± 0.2 pA/pF to 1.9 ± 0.2 pA/pF, P < 0.01, n = 8 neurons from 7 mice). We conclude that 1) SK channels are key mediators of PRR-dependent inhibition of PVNTH neurons and 2) prorenin enhances SK activity through an ERK1/2-dependent signaling pathway. These observations shed new light on PRR-mediated control of PVNTH neuronal excitability, which in turn may contribute to obesity-associated metabolic dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.