Subcellular Localization of K+ Channels in Mammalian Brain Neurons: Remarkable Precision in the Midst of Extraordinary Complexity

Abstract

Potassium channels (KChs) are the most diverse ion channels, in part due to extensive combinatorial assembly of a large number of principal and auxiliary subunits into an assortment of KCh complexes. This structural and functional diversity allows KChs to play diverse roles in neuronal function. Localization of KChs within specialized neuronal compartments defines their physiological role, and also fundamentally impacts their activity, due to localized exposure to diverse cellular determinants of channel function. Recent studies in mammalian brain reveal an exquisite refinement of KCh subcellular localization. This includes axonal KChs at the initial segment, and near/within nodes of Ranvier and presynaptic terminals, dendritic KChs found at sites reflecting specific synaptic input, and KChs defining novel compartments. Painting the remarkable diversity of KChs onto the complex architecture of mammalian neurons creates an elegant picture of electrical signal processing underlying the sophisticated function of individual neuronal compartments, and ultimately neurotransmission and behavior.

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…48,49 Indeed, they play important roles in controlling the length of action potentials and stabilizing membrane potentials. 48,49 They are also involved in the regulation of diverse cellular processes including neurotransmitter release.…”

“…48,49 Indeed, they play important roles in controlling the length of action potentials and stabilizing membrane potentials. 48,49 They are also involved in the regulation of diverse cellular processes including neurotransmitter release. 50,51 There are more than 100 mammalian genes that code for several subfamilies of K+ channels that are distributed throughout the brain and influence regional functions based on their codistribution with various neurotransmitter systems.…”

“…Kv2.2 is highly expressed in the brain and is important in the regulation of somatodendritic excitability. 49,62 When taken together, the increased expression of voltage-gated potassium channels suggests that these channels might be coregulated to promote abstinence. Our data also hint to the potential use of activators of Kv channels 63 in therapeutic interventions against METH addiction.…”

The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons

“…The voltage-gated Na + channels Nav1.2 and Nav1.6 (also known as SCN2A and SCN8A, respectively) are anchored at the AIS via the ankyrinG scaffold, which is the major organizer of this axonal subdomain (Yoshimura and Rasband, 2014;Zhou et al, 1998). A variety of voltage-gated K + channels are localized at AIS, including Kv7.2 and Kv7.3 (also known as KCNQ2 and KCNQ3, respectively), Kv1.1 and Kv1.2 (KCNA1 and KCNA2, respectively) and Kv2.1 (KCNB1), which function as modulators of action potential initiation and frequency (Devaux et al, 2004;King et al, 2014;Trimmer, 2015;Van Wart et al, 2007). The Kv7.2 and Kv7.3 channels are tethered at the AIS through ankyrinG binding (Pan et al, 2006), while the mechanisms responsible for Kv2.1 and Kv1.1/Kv1.2 enrichment are poorly understood.…”

Surface dynamics of voltage-gated ion channels

“…Many studies have shown that proper localization of ion channels along the neuronal membrane is tightly regulated by various mechanisms and is important for normal neural function, as recently reviewed. 81,113,132 Interestingly, stochastic opening of voltage-gated ion channels and lateral mobility within the plane of the membrane also influence their function and localization. A growing body of evidence accumulated in recent years shows that the surface membrane dynamics of ion channels is not just a noise but constructive variable.…”