Sinnarajah S, Dessauer C W, Srikumar D, Chen J, Yuen J, Yilma S, Dennis J C, Morrison E E, Vodyanoy V, Kehrl J H
Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA.
Nature. 2001 Feb 22;409(6823):1051-5. doi: 10.1038/35059104.
The heterotrimeric G-protein Gs couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein alpha-subunits alpha(i) and alpha(q), lack such activity for alpha(s) (refs 3-6). But several RGS proteins inhibit cAMP production by Gs-linked receptors. Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the alpha(s) family member alpha(olf) links odorant receptors to adenylyl cyclase activation. Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on alpha(olf) but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.
异源三聚体G蛋白Gs将细胞表面受体与腺苷酸环化酶的激活及环磷酸腺苷（cAMP）的产生偶联起来（参考文献1、2中有综述）。作为G蛋白α亚基α(i)和α(q)的GTP酶激活蛋白（GAP）的RGS蛋白，对α(s)缺乏这种活性（参考文献3 - 6）。但是几种RGS蛋白可抑制与Gs偶联的受体产生cAMP。我们在此报告，RGS2可降低气味刺激的嗅觉上皮细胞膜产生的cAMP，其中α(s)家族成员α(olf)将气味受体与腺苷酸环化酶激活偶联起来。出乎意料的是，RGS2降低气味诱导的cAMP产生，并非通过作用于α(olf)，而是通过抑制III型腺苷酸环化酶的活性，III型腺苷酸环化酶是嗅觉神经元中主要的腺苷酸环化酶同工型。此外，对气味刺激的嗅觉神经元进行的全细胞膜片钳记录表明，内源性RGS2对气味诱发的细胞内信号传导起负调节作用。这些结果揭示了一种控制腺苷酸环化酶活性的机制，这可能有助于嗅觉神经元辨别气味的能力。
