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Nitric oxide selectively suppresses I H currents mediated by HCN1‐containing channels
Author(s) -
KoppScheinpflug Cornelia,
Pigott Beatrice M.,
Forsythe Ian D.
Publication year - 2015
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2014.282194
Subject(s) - chemistry , superior olivary complex , nitric oxide , biophysics , hyperpolarization (physics) , depolarization , inhibitory postsynaptic potential , nucleus , nitric oxide synthase , protein subunit , intracellular , neuroscience , biochemistry , biology , stereochemistry , cochlear nucleus , organic chemistry , nuclear magnetic resonance spectroscopy , gene
Key points The superior olivary complex (SOC) exhibits a spectrum of HCN1 and HCN2 subunit expression, which generate I H currents with fast and slow kinetics, respectively. Neuronal nitric oxide synthase (nNOS) was broadly distributed across the SOC. NO hyperpolarizes the half‐activation voltage of HCN1‐mediated currents and caused a slowing of the I H current kinetics in the respective nuclei (medial and lateral superior olives and superior paraolivary nucleus). This signalling was independent of cGMP. NO also caused a depolarizing shift in the half‐activation voltage of HCN2‐mediated I H currents, increasing activation at resting potentials; this was cGMP‐dependent. Thus, NO signalling suppressed fast HCN1‐mediated currents and potentiated slow HCN2‐mediated currents, modulating the overall kinetics and magnitude of the endogenous I H .Abstract Hyperpolarization‐activated non‐specific cation‐permeable channels (HCN) mediate I H currents, which are modulated by cGMP and cAMP and by nitric oxide (NO) signalling. Channel properties depend upon subunit composition (HCN1–4 and accessory subunits) as demonstrated in expression systems, but physiological relevance requires investigation in native neurons with intact intracellular signalling. Here we use the superior olivary complex (SOC), which exhibits a distinctive pattern of HCN1 and HCN2 expression, to investigate NO modulation of the respective I H currents, and compare properties in wild‐type and HCN1 knockout mice. The medial nucleus of the trapezoid body (MNTB) expresses HCN2 subunits exclusively, and sends inhibitory projections to the medial and lateral superior olives (MSO, LSO) and the superior paraolivary nucleus (SPN). In contrast to the MNTB, these target nuclei possess an I H with fast kinetics, and they express HCN1 subunits. NO is generated in the SOC following synaptic activity and here we show that NO selectively suppresses HCN1, while enhancing I H mediated by HCN2 subunits. NO hyperpolarizes the half‐activation of HCN1‐mediated currents and slows the kinetics of native I H currents in the MSO, LSO and SPN. This modulation was independent of cGMP and absent in transgenic mice lacking HCN1. Independently, NO signalling depolarizes the half‐activation of HCN2‐mediated I H currents in a cGMP‐dependent manner. Thus, NO selectively suppresses fast HCN1‐mediated I H and facilitates a slow HCN2‐mediated I H , so generating a spectrum of modulation, dependent on the local expression of HCN1 and/or HCN2.