Nitric oxide–cyclic guanosine monophosphate–ATP-sensitive potassium channel pathway (NO–cGMP–KATP pathway) (NO–cGMP–KATP pathway)

The Nitric oxide–cyclic guanosine monophosphate–ATP-sensitive potassium channel (NO–cGMP–KATP) pathway is a fundamental signaling cascade that regulates vascular tone, pain transmission, and cellular protection [1.3.1]. It begins with the production of nitric oxide (NO), which activates soluble guanylyl cyclase (sGC) to produce the second messenger cyclic guanosine monophosphate (cGMP) [1.2.2, 1.3.3]. Elevated cGMP levels activate protein kinase G (PKG), which subsequently triggers the opening of ATP-sensitive potassium (KATP) channels [1.2.2, 1.3.2]. The resulting efflux of potassium ions causes cell membrane hyperpolarization, leading to smooth muscle relaxation in blood vessels and decreased excitability in sensory neurons [1.2.1, 1.3.1]. This pathway is a critical mediator of the effects of various drugs, including vasodilators like nitroglycerin and analgesics like diclofenac [1.1.2, 1.2.1, 1.2.5]. Dysregulation of this signaling cascade is implicated in several pathological conditions, such as hypertension, erectile dysfunction, and chronic pain [1.2.2, 1.3.1]. Pharmacological modulation of the pathway can be achieved through NO donors, sGC stimulators, phosphodiesterase inhibitors, or KATP channel openers [1.1.3, 1.2.4, 1.3.2]. However, therapeutic use of these agents requires careful management due to potential side effects like hypotension and headache [1.1.3, 1.3.1]. Overall, the NO–cGMP–KATP pathway represents a versatile therapeutic target for managing cardiovascular and neurological disorders.

Other names

NO/cGMP/KATP pathwayL-arginine/NO/cGMP/KATP pathwayNitric oxide-cGMP-KATP channel signalingNO/cGMP/PKG/KATP signaling pathway

Activation of the pathway involves NO-mediated stimulation of soluble guanylyl cyclase, increasing cGMP levels, which activates protein kinase G (PKG). PKG then promotes the opening of ATP-sensitive potassium (KATP) channels, leading to potassium efflux and membrane hyperpolarization.