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Like a handful of other neuronal types in the brain, cholinergic neurons (CNs) in the pedunculopontine nucleus (PPN) are lost during Parkinson's disease (PD). Why this is the case is unknown. One neuronal trait implicated in PD selective neuronal vulnerability is the engagement of feed-forward stimulation of mitochondrial oxidative phosphorylation (OXPHOS) to meet high bioenergetic demand, leading to sustained oxidant stress and ultimately degeneration. The extent to which this trait is shared by PPN CNs is unresolved. To address this question, a combination of molecular and physiological approaches were used. These studies revealed that PPN CNs are autonomous pacemakers with modest spike-associated cytosolic Ca2+ transients. These Ca2+ transients were partly attributable to the opening of high-threshold Ca v 1.2 Ca2+ channels, but not Ca v 1.3 channels. Ca v 1.2 channel signaling through endoplasmic reticulum ryanodine receptors stimulated mitochondrial OXPHOS to help maintain cytosolic adenosine triphosphate (ATP) levels necessary for pacemaking. Inhibition of Ca v 1.2 channels led to the recruitment of ATP-sensitive K+ channels and the slowing of pacemaking. A 'side-effect' of Ca v 1.2 channel-mediated stimulation of mitochondria was increased oxidant stress. Thus, PPN CNs have a distinctive physiological phenotype that shares some, but not all, of the features of other neurons that are selectively vulnerable in PD. • Pedunculopontine Cholinergic neurons are autonomous pacemakers. • Intracellular Ca2+ transients elevate basal mitochondrial oxidant stress. • Ca2+ control of oxidant stress is mediated by Cav1.2 containing Ca2+ channels. • Basal pacemaking relies on ATP supplied by mitochondrial oxidative phosphorylation. • Hindering mitochondrial respiration engages K-ATP channels, slowing pacemaking rate. [ABSTRACT FROM AUTHOR]