22.10
Via de sinalização de óxido nítrico
O óxido nítrico (NO), um gás inorgânico, atua como um potente segundo mensageiro na maioria dos tecidos animais e vegetais. O NO se difunde para fora…
O óxido nítrico, ou NO, é uma molécula de sinalização gasosa e um segundo mensageiro único que medeia processos como relaxamento do músculo liso, neurotransmissão e percepção visual.
Os GPCRs ligados à acetilcolina estimulam o PLC-β a induzir a produção de IP3, o que desencadeia a liberação de cálcio.
Os íons de cálcio se ligam à calmodulina para formar um complexo que ativa a NO sintase. A enzima produz NO nas células endoteliais, que se difunde nas células musculares lisas vizinhas para agir sobre elas.
O NO se liga e ativa a guanilil ciclase para produzir GMP cíclico que ativa a proteína quinase G ou PKG.
O PKG ativa uma fosfatase, que desfosforila as cadeias leves de miosina. Isso induz o dobramento das cabeças de miosina, dissociando-as dos filamentos de actina.
O PKG também inibe os canais de cálcio dependentes de IP3, reduzindo assim a concentração citosólica de cálcio. Baixos níveis de cálcio inativam as quinases de cadeia leve da miosina, impedindo a remontagem da actina-miosina e a contração muscular.
O músculo liso agora relaxa, permitindo que os vasos sanguíneos se dilatem e aumentem o fluxo sanguíneo.
View the full transcript and gain access to JoVE Core videos
Q1: How does nitric oxide function as a second messenger in cells?
Nitric oxide is a gaseous signaling molecule that diffuses out of producing cells and enters neighboring cells to generate downstream responses. NO binds and activates guanylyl cyclase, which converts GTP to cyclic GMP. This rapid increase in cGMP levels triggers protein kinase G activation, initiating the cellular response within seconds. NO's short half-life of 2-30 seconds allows it to act locally on adjacent cells.
Q2: What role does calmodulin play in nitric oxide production?
Calcium ions released from intracellular stores bind calmodulin to form a complex that activates NO synthase. This enzyme catalyzes NO production through deamination of the amino acid arginine. The calmodulin-dependent signaling pathway is essential for initiating nitric oxide synthesis in response to acetylcholine-bound GPCRs and subsequent IP3-mediated calcium release.
Q3: How does protein kinase G cause smooth muscle relaxation?
Protein kinase G activates a phosphatase that dephosphorylates myosin light chains, causing myosin heads to fold and dissociate from actin filaments. PKG also inhibits IP3-gated calcium channels, reducing cytosolic calcium concentration. Low calcium inactivates myosin light chain kinases, preventing actin-myosin reassembly and muscle contraction, resulting in smooth muscle relaxation.
Q4: Why does nitric oxide cause blood vessels to dilate?
NO diffuses from endothelial cells into neighboring smooth muscle cells, where it activates guanylyl cyclase to produce cyclic GMP. This triggers protein kinase G activation, which disassembles the actin-myosin contractile machinery. Smooth muscle relaxation allows blood vessels to dilate, increasing blood flow to tissues. This mechanism is crucial for regulating vascular tone and blood pressure.
Q5: What are the three isoforms of NO synthase and where are they found?
Endothelial NOS (eNOS) is found in endothelial cells lining blood vessels. Neuronal NOS (nNOS) is present in nerve and muscle cells. Inducible NOS (iNOS) is produced by macrophages upon exposure to various pathogens. Each isoform catalyzes NO production through arginine deamination in different tissue contexts and physiological conditions.
Q6: How do phosphodiesterase inhibitors like Viagra affect cGMP levels?
cGMP phosphodiesterase normally degrades cyclic GMP, balancing its cytosolic levels. Drugs like Viagra inhibit this enzyme, causing cGMP to remain elevated for prolonged periods. Sustained cGMP levels maintain smooth muscle relaxation in penile blood vessels, increasing blood flow and enabling erection. This mechanism demonstrates how feedback regulation of signaling molecules controls physiological responses.
Q7: How is nitroglycerine used to treat angina?
Nitroglycerine has been used since the 1860s to treat angina, a severe chest pain caused by improper blood flow to the heart muscle. The drug metabolizes into nitric oxide once inside the body. NO then dilates blood vessels, increasing blood flow to the heart and relieving chest pain. This therapeutic application demonstrates NO's critical role in regulating vascular function and tissue perfusion.