| Autor: |
Dinsdale RL; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA., Meredith AL; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
Channels (Austin, Tex.) [Channels (Austin)] 2024 Dec; Vol. 18 (1), pp. 2396346. Date of Electronic Publication: 2024 Sep 01. |
| DOI: |
10.1080/19336950.2024.2396346 |
| Abstrakt: |
Variants in KCNMA1 , encoding the voltage- and calcium-activated K + (BK) channel, are associated with human neurological disease. The effects of gain-of-function (GOF) and loss-of-function (LOF) variants have been predominantly studied on BK channel currents evoked under steady-state voltage and Ca 2+ conditions. However, in their physiological context, BK channels exist in partnership with voltage-gated Ca 2+ channels and respond to dynamic changes in intracellular Ca 2+ (Ca 2+ i ). In this study, an L-type voltage-gated Ca 2+ channel present in the brain, Ca V 1.2, was co-expressed with wild type and mutant BK channels containing GOF (D434G, N999S) and LOF (H444Q, D965V) patient-associated variants in HEK-293T cells. Whole-cell BK currents were recorded under Ca V 1.2 activation using buffering conditions that restrict Ca 2+ i to nano- or micro-domains. Both conditions permitted wild type BK current activation in response to Ca V 1.2 Ca 2+ influx, but differences in behavior between wild type and mutant BK channels were reduced compared to prior studies in clamped Ca 2+ i . Only the N999S mutation produced an increase in BK current in both micro- and nano-domains using square voltage commands and was also detectable in BK current evoked by a neuronal action potential within a microdomain. These data corroborate the GOF effect of N999S on BK channel activity under dynamic voltage and Ca 2+ stimuli, consistent with its pathogenicity in neurological disease. However, the patient-associated mutations D434G, H444Q, and D965V did not exhibit significant effects on BK current under Ca V 1.2-mediated Ca 2+ influx, in contrast with prior steady-state protocols. These results demonstrate a differential potential for KCNMA1 variant pathogenicity compared under diverse voltage and Ca 2+ conditions. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
