Abstract
Female-specific subpopulation of myelinated Ah-type baroreceptor neurons (BRNs) in nodose ganglia is the neuroanatomical base of sexual-dimorphic autonomic control of blood pressure regulation, and KCa1.1 is a key player in modulating the neuroexcitation in nodose ganglia. In this study we investigated the exact mechanisms underlying KCa1.1-mediated neuroexcitation of myelinated Ah-type BRNs in the presence or absence of estrogen. BRNs were isolated from adult ovary intact (OVI) or ovariectomized (OVX) female rats, and identified electrophysiologically and fluorescently. Action potential (AP) and potassium currents were recorded using whole-cell recording. Consistently, myelinated Ah-type BRNs displayed a characteristic discharge pattern and significantly reduced excitability after OVX with narrowed AP duration and faster repolarization largely due to an upregulated iberiotoxin (IbTX)-sensitive component; the changes in AP waveform and repetitive discharge of Ah-types from OVX female rats were reversed by G1 (a selective agonist for estrogen membrane receptor GPR30, 100 nM) and/or IbTX (100 nM). In addition, the effect of G1 on repetitive discharge could be completely blocked by G15 (a selective antagonist for estrogen membrane receptor GPR30, 3 μM). These data suggest that estrogen deficiency by removing ovaries upregulates KCa1.1 channel protein in Ah-type BRNs, and subsequently increases AP repolarization and blunts neuroexcitation through estrogen membrane receptor signaling. Intriguingly, this upregulated KCa1.1 predicted electrophysiologically was confirmed by increased mean fluorescent intensity that was abolished by estrogen treatment. These electrophysiological findings combined with immunostaining and pharmacological manipulations reveal the crucial role of KCa1.1 in modulation of neuroexcitation especially in female-specific subpopulation of myelinated Ah-type BRNs and extend our current understanding of sexual dimorphism of neurocontrol of BP regulation.
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References
Guzik P, Schneider A, Piskorski J, Klimas K, Krauze T, Marciniak R, et al. Sex differences in excess and reservoir arterial blood pressures as markers of phenotype. J Hypertens. 2019;37:2159–67.
Song JJ, Ma Z, Wang J, Chen LX, Zhong JC. Gender differences in hypertension. J Cardiovasc Transl Res. 2020;13:47–54.
Ramirez LA, Sullivan JC. Sex differences in hypertension: where we have been and where we are going. Am J Hypertens. 2018;31:1247–54.
Rauchova H, Hojna S, Kadlecova M, Vaneckova I, Zicha J. Sex differences in blood pressure of aged Ren-2 transgenic rats. Physiol Res. 2020;69:245–52.
Patrice C, Delpech R, Panjo H, Falcoff H, Saurel-Cubizolles MJ, Ringa V, et al. Differences based on patient gender in the management of hypertension: a multilevel analysis. J Hum Hypertens. 2021. https://doi.org/10.1038/s41371-20-00450. Online ahead of print.
Hinojosa-Laborde C, Craig T, Zheng W, Ji H, Haywood JR, Sandberg K. Ovariectomy augments hypertension in aging female Dahl salt-sensitive rats. Hypertension. 2004;44:405–9.
Li BY, Qiao GF, Feng B, Zhao RB, Lu YJ, Schild JH. Electrophysiological and neuroanatomical evidence of sexual dimorphism in aortic baroreceptor and vagal afferents in rat. Am J Physiol. 2008;295:R1301–10.
Li BY, Schild JH. Patch clamp electrophysiology in nodose ganglia of adult rat. J Neurosci Methods. 2002;115:157–67.
Li BY, Schild JH. Electrophysiological and pharmacological validation of vagal afferent fiber type of neurons enzymatically isolated from rat nodose ganglia. J Neurosci Methods. 2007;164:75–85.
Qiao GF, Li BY, Lu YJ, Fu YL, SChild JH. 17Beta-estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats. Am J Physiol Cell Physiol. 2009;297:C654–64.
Lu XL, Xu WX, Yan ZY, Qian Z, Xu B, Liu Y, et al. Subtype identification in acutely dissociated rat nodose ganglion neurons based on morphologic parameters. Int J Biol Sci. 2013;9:716–27.
Feng Y, Liu Y, Cao PX, Sun X, Li KX, Li XY, et al. Estrogen-dependent microRNA-504 expression and related baroreflex afferent neuroexcitation via negative regulation on KCNMB4 and KCa1.1 beta4-subunit expression. Neuroscience. 2020;442:168–82.
Santa Cruz Chavez GC, Li BY, Glazebrook PA, Kunze DL, Schild JH. An afferent explanation for sexual dimorphism in the aortic baroreflex of rat. Am J Physiol Heart Circ Physiol. 2014;307:H910–21.
Xu WX, Yu JL, Feng Y, Yan QX, Li XY, Li Y, et al. Spontaneous activities in baroreflex afferent pathway contribute dominant role in parasympathetic neurocontrol of blood pressure regulation. CNS Neurosci Ther. 2018;24:1219–30.
Liu Y, Zhou JY, Zhou YH, Wu D, He JL, Han LM, et al. Unique expression of angiotensin Type-2 receptor in sex-specific distribution of myelinated Ah-type baroreceptor neuron contributing to sex-dimorphic neurocontrol of circulation. Hypertension. 2016;67:783–91.
Liu Y, Wu D, Qu MY, He JL, Yuan M, Zhao M, et al. Neuropeptide Y-mediated sex- and afferent-specific neurotransmissions contribute to sexual dimorphism of baroreflex afferent function. Oncotarget. 2016;7:66135–48.
Yuan M, Ma MN, Wang TY, Feng Y, Chen P, He C, et al. Direct activation of tachykinin receptors within baroreflex afferent pathway and neurocontrol of blood pressure regulation. CNS Neurosci Ther. 2019;25:123–35.
Chen P, Xu B, Feng Y, Li KX, Liu Z, Sun X, et al. FGF-21 ameliorates essential hypertension of SHR via baroreflex afferent function. Brain Res Bull. 2020;154:9–20.
Liu Y, Zhao SY, Feng Y, Sun J, Lu XL, Yan QX, et al. Contribution of baroreflex afferent pathway to NPY-mediated regulation of blood pressure in rats. Neurosci Bull. 2020;36:396–406.
Li Y, Feng Y, Liu L, Li X, Li XY, Sun X, et al. The baroreflex afferent pathway plays a critical role in H2S-mediated autonomic control of blood pressure regulation under physiological and hypertensive conditions. Acta Pharmacol Sin. 2021;42:898–908.
Wen X, Yu X, Huo R, Yan QX, Wu D, Feng Y, et al. Serotonin-mediated cardiac analgesia via Ah-type baroreceptor activation contributes to silent angina and asymptomatic infarction. Neuroscience. 2019;411:150–63.
Li JN, Li XL, He J, Wang JX, Zhao M, Liang XB, et al. Sex- and afferent-specific differences in histamine receptor expression in vagal afferents of rats: a potential mechanism for sexual dimorphism in prevalence and severity of asthma. Neuroscience. 2015;303:166–77.
Li JN, Qian Z, Xu WX, Xu B, Lu XL, Yan ZY, et al. Gender differences in histamine-induced depolarization and inward currents in vagal ganglion neurons in rats. Int J Biol Sci. 2013;9:1079–88.
Hunsberger MS, Mynlieff M. BK potassium currents contribute differently to action potential waveform and firing rate as rat hippocampal neurons mature in the first postnatal week. J Neurophysiol. 2020;124:703–14.
Wu F, Sun H, Gong W, Li X, Pan Z, Shan H, et al. Genetic and pharmacological inhibition of two-pore domain potassium channel TREK-1 alters depression-related behaviors and neuronal plasticity in the hippocampus in mice. CNS Neurosci Ther. 2021;27:220–32.
Schild JH, Kunze DL. Differential distribution of voltage-gated channels in myelinated and unmyelinated baroreceptor afferents. Auton Neurosci. 2012;172:4–12.
Hay M, Kunze DL. Calcium-activated potassium channels in rat visceral sensory afferents. Brain Res. 1994;639:333–6.
Li BY, Glazebrook P, Kunze DL, Schild JH. KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents. Am J Physiol Cell Physiol. 2011;300:C1393–403.
Liu Y, Wen X, Liu SZ, Song DX, Wu D, Guan J, et al. KCa1.1-mediated frequency-dependent central and peripheral neuromodulation via Ah-type baroreceptor neurons located within nodose ganglia and nucleus of solitary tract of female rats. Int J Cardiol. 2015;185:84–7.
Zhang YY, Yan ZY, Qu MY, Guo XJ, Li G, Lu XL, et al. KCa1.1 is potential marker for distinguishing Ah-type baroreceptor neurons in NTS and contributes to sex-specific presynaptic neurotransmission in baroreflex afferent pathway. Neurosci Lett. 2015;604:1–6.
Yan ZY, He JL, Wen X, Zuo M, Guan J, Wu D, et al. Variations in afferent conduction and axonal morphometrics of aortic depressive nerve imply wider baroreflex function of low-threshold and sex-specific myelinated Ah-type baroreceptor neurons in rats. Int J Cardiol. 2015;182:23–6.
He JL, Li JN, Zuo CM, Wang LQ, Wen X, Zuo M, et al. Potentiation of 17beta-estradiol on neuroexcitability by HCN-mediated neuromodulation of fast-afterhyperpolarization and late-afterdepolarization in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons via GPR30 in female rats. Int J Cardiol. 2015;182:174–8.
Xu WX, Ban T, Wang LQ, Zhao M, Yin L, Li G, et al. KCa1.1 beta4-subunits are not responsible for iberiotoxin-resistance in baroreceptor neurons in adult male rats. Int J Cardiol. 2015;178:84–7.
Wladyka CL, Feng B, Glazebrook PA, Schild JH, Kunze DL. The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol. 2008;586:795–802.
Huo R, Xu WX, Han LM, He JL, Liu Y, Lu XL, et al. Fine tuning of calcium on membrane excitation of baroreceptor neurons in rats. Int J Cardiol. 2014;174:883–7.
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This research was funded by National Natural Science Foundation of China (31171122, 81573431, and 81971326) to BYL.
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LQW, ZQ, and BYL designed the study, conducted patch recording, and interpreted observation. HLM, MZ, HDL, and CPC performed ovariectomized surgery, neurons isolation, and immunostaining, prepared recording solution, and statistical evaluation. DLL, XLL, and BYL draft and revised the manuscript. ZQ, XLL, and BYL finalized the manuscript. BYL provided research funding.
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Wang, Lq., Qian, Z., Ma, Hl. et al. Estrogen-dependent KCa1.1 modulation is essential for retaining neuroexcitation of female-specific subpopulation of myelinated Ah-type baroreceptor neurons in rats. Acta Pharmacol Sin 42, 2173–2180 (2021). https://doi.org/10.1038/s41401-021-00722-4
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DOI: https://doi.org/10.1038/s41401-021-00722-4
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