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Inhibition of endoplasmic reticulum function in PVN by thapsigargin increases neuronal excitability and sympathetic nerve activity (1125.4)
Author(s) -
Larson Robert,
Gui Le,
Chapp Andrew,
Huber Michael,
Zhu Jianhua,
Cheng Zixi,
Shan Zhiying,
Chen QingHui
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1125.4
Subject(s) - rostral ventrolateral medulla , microinjection , medicine , thapsigargin , endocrinology , endoplasmic reticulum , chemistry , nucleus , medulla oblongata , central nervous system , neuroscience , biology , biochemistry
Control of sympathetic outflow by paraventricular nucleus (PVN) is partially mediated through a monosynaptic axon projecting to the rostral ventrolateral medulla (PVN‐RVLM). Here we investigated the role of thapsigargin (TG), the endoplasmic reticulum (ER) Ca2+ ATPase inhibitor, in regulating the excitability of PVN‐RVLM neurons under brain slice preparation. In current‐clamp recordings, graded current injections evoked graded increases in spike frequency. Maximum discharge was evoked by +200 pA injections and averaged 22 ± 2 Hz (n=7) and was significantly greater (P < 0.05) in the presence of TG (0.5 µM) (31 ± 3 Hz, n=9). The effect of ER Ca2+ store depletion in regulating renal SNA (RSNA) and mean arterial pressure (MAP) was assessed by bilateral PVN microinjection of TG in anesthetized rats. PVN injection of TG (0.15, 0.3 0.75 and 1.5 nmol/100nl) increased RSNA and MAP in a dose‐dependent manner. Maximum increases in RSNA and MAP elicited by PVN TG (0.75 nmol/100nl; n=3) were 105 ± 31% and 18 ± 11 mmHg respectively. Pre‐treatment with CyPPA (5 nmol/100 nl), a small conductance, Ca2+ activated K (SK) channel activator (n=3), attenuated the PVN TG evoked sympathoexcitatory and pressor responses (7 ± 7% for RSNA and 4 ± 7 mmHg for MAP). PVN CyPPA did not significantly alter baseline RSNA and MAP. Our data indicate that inhibition of ER function with TG enhances in vitro excitability of PVN‐RVLM neurons and increases in vivo RSNA and MAP. The effect of TG on the excitability of PVN neurons and SNA through ER Ca2+ store depletion may involve reduced SK channel activity. Grant Funding Source : Supported by AHA10SDG2640130