Modulation of Hyperpolarization-Activated Inward Current and Thalamic Activity Modes by Different Cyclic Nucleotides

Abstract

The hyperpolarization-activated inward current, Ih, plays a key role in the generation of rhythmic activities in thalamocortical (TC) relay neurons. Cyclic nucleotides, like 3′,5′-cyclic adenosine monophosphate (cAMP), facilitate voltage-dependent activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels by shifting the activation curve of Ih to more positive values and thereby terminating the rhythmic burst activity. The role of 3′,5′-cyclic guanosine monophosphate (cGMP) in modulation of Ih is not well understood. To determine the possible role of the nitric oxide (NO)-sensitive cGMP-forming guanylyl cyclase 2 (NO-GC2) in controlling the thalamic Ih, the voltage-dependency and cGMP/cAMP-sensitivity of Ih was analyzed in TC neurons of the dorsal part of the lateral geniculate nucleus (dLGN) in wild type (WT) and NO-GC2-deficit (NO-GC2−/−) mice. Whole cell voltage clamp recordings in brain slices revealed a more hyperpolarized half maximal activation (V1/2) of Ih in NO-GC2−/− TC neurons compared to WT. Different concentrations of 8-Br-cAMP/8-Br-cGMP induced dose-dependent positive shifts of V1/2 in both strains. Treatment of WT slices with lyase enzyme (adenylyl and guanylyl cyclases) inhibitors (SQ22536 and ODQ) resulted in further hyperpolarized V1/2. Under current clamp conditions NO-GC2−/− neurons exhibited a reduction in the Ih-dependent voltage sag and reduced action potential firing with hyperpolarizing and depolarizing current steps, respectively. Intrathalamic rhythmic bursting activity in brain slices and in a simplified mathematical model of the thalamic network was reduced in the absence of NO-GC2. In freely behaving NO-GC2−/− mice, delta and theta band activity was enhanced during active wakefulness (AW) as well as rapid eye movement (REM) sleep in cortical local field potential (LFP) in comparison to WT. These findings indicate that cGMP facilitates Ih activation and contributes to a tonic activity in TC neurons. On the network level basal cGMP production supports fast rhythmic activity in the cortex.

The Hyperpolarization-Activated HCN4 Channel is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System

“…The HCN4-KO represents the bottom-up mechanism since the hyperpolarization of TC cells following loss of HCN4 resulted in low-frequent cortical oscillations. Furthermore, it is interesting to note that the SWD frequency (7–11 Hz) in genetic epilepsy models and the lower delta frequency oscillations (1–4 Hz) in TDC models are associated with increased (Kanyshkova et al 2012) and decreased (Datunashvili et al 2018; Zobeiri, Chaudhary et al 2018) availability of I h in TC neurons. Thalamic oscillatory activity is shaped by phasic inhibition of TC neurons via GABAergic NRT neurons and IN (von Krosigk et al 1993; Lorincz et al 2009).…”

Characterization of Inhibitory Effectiveness in Hyperpolarization-Activated Cation Currents by a Group of ent-Kaurane-Type Diterpenoids from Croton tonkinensis

“…We further performed current-clamp voltage recordings in attempts to test if croton-03 could produce any perturbations on sag potential in these cells. Sag potential in response to hyperpolarizing current stimulus has been described to be intimately linked to the occurrence of I h in different types of central neurons [20,33,34]. As shown in Figure 6, under our experimental condition, when the whole-cell voltage recordings were firmly established, a long-step hyperpolarizing current injection with the amplitude of around 25 pA was found to induce sag potential (i.e., drop down to a lower level in the membrane potential upon hyperpolarizing current stimuli).…”

“…The rat INS-1 cell line (clone 832/13) was kindly provided by Christopher B. Newgard, Duke University, Durham, NC. Cells were plated in 10-cm plate and grown in RPMI-1640 medium supplemented with 11.1 mM D-glucose, 10% fetal bovine serum, 10 mM HEPES, 2 mM L-glutamine, 1 mM sodium pyruvate, and 50 µM β-mercaptoethanol [34]. The experiments were commonly made five or six days after cells had been cultured (60-80% confluence).…”

Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents

“…Hyperpolarization-activated cation current (I h ) is a key determinant of repetitive electrical activity in heart cells, and in a variety of neurons, neuroendocrine, and endocrine cells [21][22][23][24][25][26][27]. This type of ionic current can conduct Na + and K + ions, and the current activation of its own accord can act to depolarize membrane potential, thereby adequately reaching the threshold required for action potential generation [22,28].…”

“…It is regarded to be carried by channels of the hyperpolarization-activated cyclic nucleotide-gated (HCN) gene family, named HCN1, HCN2, HCN3, and HCN4 [28]. Generation of HCN1-, HCN2-, and HCN4-deficient mice has highlighted the important role of these channels in regulation of pacemaker activity [26,29]. Of interest, previous reports have shown the ability of either MEL55A, an inhibitor of I h , or dexmedetomidine to ameliorate OXAL-induced pain sensation [18,19,30].…”