Kv2 Channel Regulatory Subunits Confer Drug Resistance and Modulate Electrical Signaling

Kernkonzepte

Kv2 channel regulatory subunits (KvS) confer resistance to the Kv2-selective blocker RY785, while remaining sensitive to the Kv2-selective modulator GxTX, enabling pharmacological isolation of Kv2/KvS heteromeric channels from Kv2-only channels in native neurons.

Zusammenfassung

The content describes a method to pharmacologically distinguish conductances of Kv2/KvS heteromeric channels from Kv2-only channels. Key insights:

1. Kv2.1/Kv8.1 heteromeric channels are resistant to the Kv2-selective blocker RY785 but sensitive to the Kv2-selective modulator GxTX. This resistance is shared across KvS subunit families (Kv5, Kv6, Kv8, Kv9).

2. In mouse superior cervical ganglion (SCG) neurons, which lack substantial KvS expression, RY785 blocks most of the Kv2-like conductance, suggesting SCG neurons have predominantly Kv2-only channels.

3. In mouse nonpeptidergic dorsal root ganglion (DRG) neurons and human DRG neurons, a substantial fraction (>50%) of the Kv2-like conductance is RY785-resistant but GxTX-sensitive, indicating the presence of Kv2/KvS heteromeric channels.

4. The RY785-resistant, GxTX-sensitive currents in DRG neurons exhibit biophysical properties consistent with Kv2/KvS heteromers, such as slower deactivation kinetics.

5. These findings suggest that drugs targeting KvS subunits could selectively modulate electrical activity in subsets of Kv2-expressing cell types.

Statistiken

1 μM RY785 inhibited 88 ± 5% of the voltage-gated current in mouse superior cervical ganglion neurons.
In mouse nonpeptidergic dorsal root ganglion neurons, 1 μM RY785 inhibited 29 ± 3% of the voltage-gated current, and the remaining 58 ± 3% was sensitive to 100 nM GxTX.
In human dorsal root ganglion neurons, 1 μM RY785 inhibited 24 ± 2% of the voltage-gated current, and the remaining 76 ± 2% was sensitive to 100 nM GxTX.

Zitate

"Kv2.1/Kv8.1 heteromeric channels are resistant to RY785 and sensitive to GxTX."
"A subunit from each KvS family is resistant to RY785 but sensitive to GxTX."
"Mouse nociceptors have KvS-like conductances."
"Human somatosensory neurons have KvS-like conductances."

Wichtige Erkenntnisse aus

A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers

by Stewart,R. G... um www.biorxiv.org 02-02-2024

https://www.biorxiv.org/content/10.1101/2024.01.31.578214v3

Tiefere Fragen

What are the potential therapeutic implications of selectively targeting KvS-containing channels

Targeting KvS-containing channels selectively could have significant therapeutic implications in various pathological conditions. Since KvS subunits show tissue- and cell-specific expression patterns, drugs targeting these subunits could offer greater specificity in modulating neuronal excitability. This specificity could lead to more targeted treatments for conditions such as epilepsy, neuropathic pain, retinal cone dystrophy, and other disorders where KvS subunits have been implicated. By modulating the activity of subsets of Kv2-expressing cell types, drugs targeting KvS subunits could potentially offer a more refined and effective therapeutic approach with fewer side effects compared to non-specific Kv2-targeted drugs.

How might the differential expression and regulation of KvS subunits across cell types contribute to the diverse physiological roles of Kv2 channels

The differential expression and regulation of KvS subunits across cell types likely contribute to the diverse physiological roles of Kv2 channels. KvS subunits, which form heterotetrameric channels with Kv2 subunits, have unique expression patterns that overlap with Kv2.1 or Kv2.2 expression in specific tissues and cell types. This differential expression allows for the modulation of Kv2 channel function in a cell-specific manner. The presence of KvS subunits in certain cell types can alter the biophysical properties of Kv2 channels, leading to distinct conductances and functional effects. Additionally, the tissue-specific expression of KvS subunits suggests that they play specialized roles in different organ systems, contributing to the wide-ranging functions of Kv2 channels in vision, seizure suppression, pain signaling, and other physiological processes.

Could the RY785/GxTX pharmacology be used to investigate the developmental or activity-dependent regulation of Kv2/KvS channel composition in native neurons

The RY785/GxTX pharmacology could be a valuable tool for investigating the developmental or activity-dependent regulation of Kv2/KvS channel composition in native neurons. By using this pharmacological approach to selectively target Kv2/KvS channels and Kv2-only channels, researchers can study the changes in channel composition under different conditions. For example, during development, the expression levels of KvS subunits may change, leading to alterations in the proportion of Kv2/KvS channels in specific cell types. Similarly, activity-dependent regulation of KvS subunits could impact the functional properties of Kv2 channels in response to neuronal activity. By applying the RY785/GxTX approach in native neurons at different developmental stages or under various activity conditions, researchers can elucidate the dynamic regulation of Kv2/KvS channel composition and its implications for neuronal function.