Leinders-Zufall T, Shepherd G M, Zufall F
Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Proc Biol Sci. 1996 Jun 22;263(1371):803-11. doi: 10.1098/rspb.1996.0120.
Recent evidence has indicated a significant role for the cGMP second messenger system in vertebrate olfactory transduction but no clear functions have been identified for cGMP so far. Here, we have examined the effects of 8-Br-cGMP and carbon monoxide (CO) on odour responses of salamander olfactory receptor neurons using perforated patch recordings. We report that 8-Br-cGMP strongly down-regulates the odour sensitivity of the cells, with a K1/2 of 460 nM. This adaptation-like effect can be mimicked by CO, an activator of soluble guanylyl cyclase, with a K1/2 of 1 microM. Sensitivity modulation is achieved through a regulatory chain of events in which cGMP stimulates a persistent background current due to the activation of cyclic nucleotide-gated channels. This in turn leads to sustained Ca2+ entry providing a negative feedback signal. One consequence of the Ca2+ entry is a shift to the right of the stimulus-response curve and a reduction in saturating odour currents. Together, these two effects can reduce the sensory generator current by up to twenty-fold. Thus, cGMP functions to control the gain of the G-protein coupled cAMP pathway. Another consequence of the action of cGMP is a marked prolongation of the odour response kinetics. The effects of CO/cGMP are long-lasting and can continue for minutes. Hence, we propose that cGMP helps to prevent saturation of the cell's response by adjusting the operational range of the cAMP cascade and contributes to olfactory adaptation by decreasing the sensitivity of olfactory receptor cells to repeated odour stimuli.
最近的证据表明，环磷酸鸟苷（cGMP）第二信使系统在脊椎动物嗅觉转导中起重要作用，但迄今为止尚未确定cGMP的明确功能。在这里，我们使用穿孔膜片钳记录法研究了8-溴环磷酸鸟苷（8-Br-cGMP）和一氧化碳（CO）对蝾螈嗅觉受体神经元气味反应的影响。我们报告称，8-Br-cGMP强烈下调细胞的气味敏感性，其半数抑制浓度（K1/2）为460 nM。这种类似适应的效应可被可溶性鸟苷酸环化酶的激活剂CO模拟，其K1/2为1 microM。敏感性调节是通过一系列调节事件实现的，其中cGMP由于环核苷酸门控通道的激活而刺激持续的背景电流。这反过来又导致持续的Ca2+内流，提供一个负反馈信号。Ca2+内流的一个结果是刺激-反应曲线向右移动，饱和气味电流降低。这两种效应共同作用可使感觉发生器电流降低多达20倍。因此，cGMP的作用是控制G蛋白偶联的环磷酸腺苷（cAMP）途径的增益。cGMP作用的另一个结果是气味反应动力学显著延长。CO/cGMP的作用是持久的，可持续数分钟。因此，我们提出，cGMP通过调节cAMP级联反应的工作范围来帮助防止细胞反应饱和，并通过降低嗅觉受体细胞对重复气味刺激的敏感性来促进嗅觉适应。
