HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

Abstract

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at the subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can be bidirectionally modulated by a HCN channel blocker, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mouse cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC50 40 µM; estimated endogenous cAMP concentration 13 µM). In addition, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily by altering the resting membrane potential and are associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators with an opportunity to finely tune energy consumption and temporal delays across axons in the brain.

Evidence for Effective Inhibitory Actions on Hyperpolarization-Activated Cation Current Caused by Ganoderma Triterpenoids, the Main Active Constitutents of Ganoderma Spores

“…GTs was also previously reported to exert analgesic actions [11,53], which could be possibly associated with its inhibition of I h in different types of sensory neurons. It is also important to note that the I h was expressed either in urinary bladder, ureter and renal pacemaker tissue or in different types of tumor cells (e.g., lung carcinoma cells) [34,54,55,56,57]; at extent GTs-induced block of I h is linked to its antineoplastic actions or impairments in urine excretion remains to be imperatively evaluated.…”

“…Hyperpolarization-activated cation current ( I h ) has been well recognized as a key determinant of repetitive electrical activity in heart cells and in an array of sensory or central neurons, and neuroendocrine or endocrine cells [26,27,28,29,30,31,32,33,34,35]. This current is a mixed inward Na + /K + current, which is sensitive to block by CsCl, ivabradine or zatebradine [29,36,37], and the rise in this current can consequently act to depolarize membrane potential to threshold required for the generation of action potential (AP) [28,30,31,33].…”

Nitrergic modulation of ion channel function in regulating neuronal excitability

“…HCN (I h current ) : HCN 1–4 channels are classically activated by cyclic nucleotides, including cGMP and cAMP, which generate an inward current [termed hyperpolarization-activated current (I h )] at membrane potentials negative to approximately −50 mV. I h helps setting the resting membrane potential and thereby influences neuronal excitability, synaptic integration, and other neuronal properties [ 52 , 53 ]. The mechanisms and importance of their regulation has been studied in multiple systems, including Aplysia [ 54 ], and in the mammalian brain, this channel has been described in some neuronal populations as a major regulator of neuronal intrinsic excitability [ 53 ].…”

Modulation of Neural Microcircuits That Control Complex Dynamics in Olfactory Networks

“…Neuromodulatory mechanisms are numerous and target different aspects of neuronal activity to produce diverse effects, but ultimately each fine-tunes the information being transferred ( Figure 1 ). The largest group of neuromodulators bind to GPCRs and activate G proteins that initiate intracellular signaling cascades via second messengers (Chen et al, 2006 ; Newton et al, 2016 ; Byczkowicz et al, 2019 ; Moro et al, 2020 ). Subsequent to GPCR binding, effects include changes in gene expression (Fukuchi et al, 2015 ), ion channel properties that impact action potential propagation (Burke and Bender, 2019 ), and even interaction of G βγ with the soluble NSF attachment protein REceptor, or SNARE complex, inhibiting neurotransmitter release (Zurawski et al, 2019 ; Hamm and Alford, 2020 ).…”