AI Article Synopsis
- Large conductance, calcium/voltage-gated potassium channels (BK) play a vital role in various body functions and are particularly important in smooth muscle (SM) due to the high expression of accessory beta1 subunits.
- Pharmaceutical development targeting beta1 may help treat smooth muscle disorders like hypertension, but previous compounds have shown low effectiveness and unwanted side effects.
- Research identified a potent activator and a potent antagonist for beta1-dependent BK, providing initial evidence that both types of compounds can effectively modulate BK activity in a targeted manner.
Article Abstract
Large conductance, calcium/voltage-gated potassium channels (BK) regulate critical body processes, including neuronal, secretory and smooth muscle (SM) function. While BK-forming alpha subunits are ubiquitous, accessory beta1 subunits are highly expressed in SM. This makes beta1 an attractive target for pharmaceutical development to treat SM disorders, such as hypertension or cerebrovascular spasm. Compounds activating BK via beta1 have been identified, yet they exhibit low potency and off-target effects while antagonists that limit agonist activity via beta 1 remain unexplored. Beta1-dependent BK ligand-based pharmacophore modeling and ZINC database searches identified 15 commercially available hits. Concentration-response curves on BK alpha + beta1 subunit-mediated currents were obtained in CHO cells. One potent (EC = 20 nM) and highly efficacious activator (maximal activation = ×10.3 of control) was identified along with a potent antagonist (K = 3.02 nM), both of which were dependent on beta1. Our study provides the first proof-of-principle that an agonist/antagonist pair can be used to control beta1-containing BK activity.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464842 | PMC |
| http://dx.doi.org/10.1016/j.bmc.2022.116876 | DOI Listing |
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