What are the peer review resources regarding ion channels and G protein (Guanine nucleotide-binding protein)-coupled receptors to signal transduction in target medication?

From the Guidelines

To effectively develop targeted medications, it is crucial to focus on the most recent and highest quality studies regarding ion channels and G protein signal transduction, such as the 2021 British Society of Gastroenterology guidelines on the management of irritable bowel syndrome 1. When considering the development of targeted medications, several key points must be taken into account:

• Ion channels, such as calcium, sodium, and potassium channels, play a critical role in controlling membrane potential and cellular excitability through selective ion passage.
• G proteins act as molecular switches that transduce signals from membrane receptors to intracellular effectors, and their complex downstream signaling cascades are essential for drug development.
• Successful medications that target these pathways include calcium channel blockers (amlodipine, verapamil), sodium channel modulators (lidocaine, lamotrigine), potassium channel openers (minoxidil), and G protein-coupled receptor (GPCR) targeting drugs (beta-blockers like metoprolol, angiotensin receptor blockers like losartan). Some of the key drugs used for the treatment of irritable bowel syndrome with constipation (IBS-C) include:
• Linaclotide, a peptide that acts as a guanylate cyclase-C agonist, which has been shown to be superior to placebo in improving abdominal pain and increasing bowel movements in patients with IBS-C 1.
• Lubiprostone, a prostaglandin E1 derivative, which activates chloride type 2 channels and has been shown to be effective in improving abdominal pain and bowel movements in patients with IBS-C 1.
• Plecanatide, another guanylate cyclase-C agonist, which has been shown to be effective in improving abdominal pain and bowel movements in patients with IBS-C, but not in improving bloating 1.
• Tenapanor, a small molecule inhibitor of the gastrointestinal sodium-hydrogen exchanger-3, which has been shown to be effective in improving abdominal pain and bowel movements in patients with IBS-C 1. The development of targeted medications for IBS-C should prioritize the use of these drugs, which have been shown to be effective in improving symptoms and quality of life for patients with this condition, as demonstrated by the 2021 British Society of Gastroenterology guidelines 1.

From the Research

Ion Channels and G Protein-Coupled Receptors

• Ion channels are membrane proteins involved in various physiological processes, including neurotransmission, muscle contraction, and cell proliferation 2
• They are attractive targets for drug discovery and safety pharmacology due to their broad distribution in the human body and physiological roles 2
• G protein-coupled receptors (GPCRs) can regulate ion channels through direct or indirect mechanisms, including physical interactions between G-protein subunits and the channel protein 3

Regulation of Ion Channels by G Proteins

• G proteins can modulate ion channels via second messengers and protein kinases, or through direct physical interactions between G-protein subunits and the channel protein 3
• The G-protein beta gamma subunits (G beta gamma) are the active regulators of several voltage-dependent Ca(2+) channels and the G-protein-activated K(+) channels 3
• Ion channels are one of the six major pharmacological targets, along with G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes, and transporters 4

Cross-Talk between GPCRs and Ion Channels

• The function of many ion channels is under dynamic control by coincident activation of GPCRs, particularly those coupled to the Gαs and Gαq family members 5
• GPCRs engage a myriad of signaling pathways that involve protein kinases A and C (PKC) and, through PKC and interaction with β-arrestin, Src kinase, and hence the mitogen-activated-protein-kinase cascades 5
• G proteins have become a major focus of current research, and it is now evident that ion channel permeability is one such effector response 6

Ion Channel Regulation and Drug Discovery

• The search for the development of new and more specific therapeutic approaches is strongly pursued, and the combination of in silico methods and patch clamp experiments can help address drug discovery and safety issues regarding ion channels 2
• The Concise Guide to PHARMACOLOGY 2021/22 provides concise overviews of the key properties of nearly 1900 human drug targets, including ion channels and G protein-coupled receptors 4