GIRK Related Drug Discovery Products

The excitability of neurons, cardiac myocytes, and endocrine cells is regulated by signal transduction involving inhibitory (Gi/o) G proteins. This process is essential for controlling mood and cognition, nociception and antinociception, reward, energy homeostasis, motor activity and coordination, hormone secretion, and cardiac output. A typical effector for Gi/o-dependent signaling pathways in the heart and nervous system is the GIRK/Kir3 channel. Dysregulation of GIRK signaling may be a factor in specific human diseases and disorders, according to studies of mutant mice and a more constrained set of linkage analyses.

Creative Biolabs can offer high-quality GIRK in vitro assays and related products to contribute to the success of drug discovery:

• GIRK Assays
• Ion Channel Cell Lines
• Ion Channel Membranes
• Membrane Protein Tools

Overview of GIRK

The broad family of inwardly rectifying K⁺ channels is GIRK channels (Kir1-Kir7). A change in the channel's current-voltage relationship at the reversal potential is referred to as "inward rectification." The outward current is very tiny compared to the inward current at membrane potentials considerably below the equilibrium potential for K⁺ (E_K) and potentials well above E_K. This rectification results from intracellular Mg²⁺ and polyamines blocking the central pore at potentials higher than E_K. A typical neuron's resting membrane potential is positive to E_K under physiological circumstances, and a little outward K⁺ current through GIRK channels reduces a neuron's excitability. These channels are opened up by a variety of neurotransmitters, including acetylcholine, dopamine, opioids, serotonin, somatostatin, adenosine, and GABA. These neurotransmitters do this by stimulating the cognate G protein-coupled receptors (GPCRs), which pair specifically to pertussis toxin (PTX)-sensitive heterotrimeric G proteins that open up GIRK channels.

GIRK Drug Discovery

Numerous disorders, including epilepsy, addiction, Down's syndrome, ataxia, and Parkinson's disease, have GIRK channels as part of their pathogenesis. Gaining GIRK function can significantly lower neural activity, as is thought to happen in Down's syndrome, whereas losing GIRK function can result in excessive neuronal excitability, as in epilepsy. A model of Parkinson's illness serves as an illustration of how loss of selectivity can result in aberrant ion fluxes via GIRK channels, such as an abnormal Na+ influx that leads to cell death.

• Changes in the excitability of neurons

When given an injection of a pro-convulsive GABAA receptor antagonist, GIRK2-knockout mice have a predilection for generalized seizures as well as spontaneous convulsions. On the other hand, electroconvulsive shock increases the expression of GIRK channels, which might offer neuroprotection from unwarranted activity. Galanin type 2 receptor stimulation that opens GIRK channels stops rat-kindled epileptogenesis, indicating GIRK channels as a potential new target for anticonvulsants.

• Addiction

The acute rewarding effects and/or adaptation that follow chronic exposure to addictive substances that act through GPCRs are hypothesized to be influenced by GIRK channels. GIRK channels are opened up by opioids and GHB, which disinhibits dopaminergic neurons. Morphine inhibits the firing of these cells, which eventually results in the disinhibition of dopaminergic neurons, via stimulating μ-opioid receptors that are specifically expressed on interneurons of the VTA.