Inwardly Rectifying Potassium Channel Related Drug Discovery Products

Inwardly rectifying potassium (Kir) channels play two key physiological roles: they regulate K⁺ transport across membranes and stabilize the resting membrane potential close to the K⁺ equilibrium potential. Particularly in the kidney, Kir1.x is involved in transepithelial membrane trafficking. Kir2.x regulates the heart's and brain's level of excitability. The effects of several G-protein-coupled receptors on electrical activity in cardiac, neuronal, and neurosecretory cells are mediated by Kir3.x channels, which are G-protein activated. The Kir6.x and SUR subunit-containing ATP-sensitive K⁺ (KATP) channels, which link cellular metabolism to electrical activity and K⁺ fluxes, are controlled by cytosolic nucleotides. They are crucial for the modulation of vascular smooth muscle tone, the response to cardiac and cerebral ischaemia, and the regulation of insulin secretion. Kir4.1, Kir.5.x, and Kir7.x channels' physiological functions are not yet fully understood. Creative Biolabs can offer inwardly rectifying potassium channel related products to contribute to the success of drug discovery.

Overview of Inwardly Rectifying Potassium Channel

• GIRK

G-protein-gated inward rectifier K⁺ (GIRK) is the Kir3.x. Acetylcholine-activated inward rectifier current (I_K,Ach) is mediated by the Kir channel subunits Kir3.1 and Kir3.4 (GIRK1/4) and is present in cardiac atrial and nodal myocytes. Acetylcholine and other muscarinic substances that attach to the muscarinic M2 receptor induce the Giβγ subunits to get separated from the Giα subunit, which then binds to and activates I_K,Ach. Kir3.1, Kir3.2, and Kir3.3 subunits are expressed in the amygdala, ventral tegmental region, cortex, hippocampus, cerebellum, and spinal cord in the central nervous system (CNS) and peripheral nervous system. The most widely distributed GIRK channels in the CNS are Kir3.1/Kir3.2 heterotetramers (GIRK1/2), which are activated by a variety of neuromodulators, including somatostatin, dopamine, endorphins, and endocannabinoids. The presynaptic resting membrane potential shifts more negatively after GPCR stimulation due to the activation of the GIRK1/2 channels in the presynaptic nerve terminal. As a result, the generation of spontaneous action potentials is reduced, and the release of excitatory neurotransmitters is inhibited.

Fig.1 GIRK channels.^1,2

• KATP

As K⁺-selective channels that are activated under circumstances that result in an increase in intracellular ADP but are blocked during increases in ATP, KATP channels were first identified in cardiomyocytes. Four Kir6.2 or four Kir6.1 subunits and regulatory sulfonylurea receptor (SUR) subunits make up KATP channels. Additionally expressed in the pituitary, basal ganglia, cerebral cortex, hippocampus, and basal forebrain are the KATP channels in the CNS. The brain expresses both the Kir6.1 and Kir6.2 subunits. KATP channels in the hypothalamus are crucial in controlling the release of hormones like glucagon and adrenaline. Hypothalamic neurons experience a drop in intracellular ATP levels when brain glucose levels decline, which is followed by the activation of KATP channels. Neuronal hyperpolarization that results from this stimulation of the autonomic nervous system triggers the production of the hormones glucagon and epinephrine, which act as insulin's antagonists and raise blood glucose levels.

References

1. Kotajima-Murakami, Hiroko, Soichiro Ide, and Kazutaka Ikeda. "GIRK channels as candidate targets for the treatment of substance use disorders." Biomedicines 10.10 (2022): 2552.
2. Image retrieved from Figure 1 "GIRK channel subunits in the brain and signal transduction of addictive substances through GIRK channels." Kotajima-Murakami, et al. 2022, used under CC BY 4.0. The original image was modified by extracting and using part b and the title was changed to " GIRK channels.".