FIGURE 1.

Hypothetical HCN channel-related pathogenic cascade in SNc dopaminergic neurons in PD. (A) HCN channels modulate the electrophysiological activities of SNc dopaminergic neurons. Dopaminergic neurons display tonic irregular single-spike firing and phasic burst firing in vivo, and slow, regular, pacemaker activity in vitro. HCN channels blockade with ZD7288 reduces the amplitude of I_h, leading to cell membrane hyperpolarization, decreased firing activity, or even increased burst firing in vitro. HCN channels also regulate neuronal oscillatory activity. (B) Proposed mechanism for the involvement of HCN channels in the neurotoxic effects of MPP⁺. MPP⁺ accumulates in mitochondria, where it inhibits complex I, causing ATP depletion, increased ROS formation, and oxidative stress. The decreased cellular ATP and cAMP concentration leads to the opening of K-ATP channels and inhibition of HCN channels. This results in hyperpolarization of the cell membrane and reduction in the spontaneous firing of dopaminergic neurons. MPP⁺ is also speculated to directly interact with HCN channels, causing I_h inhibition. This further leads to the amplification of SCRs by potentiating EPSP and depressing IPSP, which results in an imbalance of intracellular calcium homeostasis. This in turn potentiates oxidative stress and ultimately leads to cell death.