Nitric oxide selectively suppresses IH currents mediated by HCN1 containing channels

Hyperpolarization-activated non-specific cation permeable channels (HCN) mediate IH currents which are modulated by cGMP, cAMP and by nitric oxide (NO) signalling. Channel properties depend upon subunit composition (HCN1-4 and accessory subunits) as demonstrated in expression systems, however 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 IH 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 IH with fast kinetics, and express HCN1 subunits. NO is generated in the SOC following synaptic activity and here we show that NO selectively suppresses HCN1, while enhancing IH mediated by HCN2 subunits. NO hyperpolarizes the half-activation of HCN1-mediated currents and slows the kinetics of native IH currents in the MSO, LSO and SPN. This modulation was independent of cGMP and absent in transgenic mice lacking HCN1. Independently, NO signalling depolarized the half-activation of HCN2-mediated IH currents in a cGMP-dependent manner. Thus NO selectively suppresses fast HCN1-mediated IH and facilitates a slow HCN2-mediated IH, so generating a spectrum of modulation, dependent on the local expression of HCN1 and/or HCN2 and the actions of NO signalling.




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