White R E, Lee A B, Shcherbatko A D, Lincoln T M, Schonbrunn A, Armstrong D L
Laboratory of Cellular and Molecular Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Nature. 1993 Jan 21;361(6409):263-6. doi: 10.1038/361263a0.
Natriuretic peptides inhibit the release and action of many hormones through cyclic guanosine monophosphate (cGMP), but the mechanism of cGMP action is unclear. In frog ventricular muscle and guinea-pig hippocampal neurons, cGMP inhibits voltage-activated Ca2+ currents by stimulating phosphodiesterase activity and reducing intracellular cyclic AMP; however, this mechanism is not involved in the action of cGMP on other channels or on Ca2+ channels in other cells. Natriuretic peptide receptors in the rat pituitary also stimulate guanylyl cyclase activity but inhibit secretion by increasing membrane conductance to potassium. In an electrophysiological study on rat pituitary tumour cells, we identified the large-conductance, calcium- and voltage-activated potassium channels (BK) as the primary target of another inhibitory neuropeptide, somatostatin. Here we report that atrial natriuretic peptide also stimulates BK channel activity in GH4C1 cells through protein dephosphorylation. Unlike somatostatin, however, the effect of atrial natriuretic peptide on BK channel activity is preceded by a rapid and potent stimulation of cGMP production and requires cGMP-dependent protein kinase activity. Protein phosphatase activation by cGMP-dependent kinase could explain the inhibitory effects of natriuretic peptides on electrical excitability and the antagonism of cGMP and cAMP in many systems.
利钠肽通过环磷酸鸟苷（cGMP）抑制多种激素的释放和作用，但其cGMP作用机制尚不清楚。在蛙心室肌和豚鼠海马神经元中，cGMP通过刺激磷酸二酯酶活性和降低细胞内环磷酸腺苷（cAMP）来抑制电压激活的Ca2+电流；然而，这种机制并不参与cGMP对其他通道或其他细胞中Ca2+通道的作用。大鼠垂体中的利钠肽受体也刺激鸟苷酸环化酶活性，但通过增加细胞膜对钾的电导来抑制分泌。在一项对大鼠垂体肿瘤细胞的电生理研究中，我们确定大电导、钙和电压激活的钾通道（BK）是另一种抑制性神经肽——生长抑素的主要靶点。在此我们报告，心房利钠肽也通过蛋白质去磷酸化刺激GH4C1细胞中的BK通道活性。然而，与生长抑素不同的是，心房利钠肽对BK通道活性的影响之前会迅速且强烈地刺激cGMP的产生，并且需要依赖cGMP的蛋白激酶活性。依赖cGMP的激酶激活蛋白磷酸酶可以解释利钠肽对电兴奋性的抑制作用以及在许多系统中cGMP和cAMP之间的拮抗作用。
