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J. Biol. Chem., Vol. 280, Issue 3, 1808-1816, January 21, 2005

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Modeling of G_s and G_i Regulation of Human Type V and VI Adenylyl Cyclase^*

Misty Chen-Goodspeed, Abolanle N. Lukan, and Carmen W. Dessauer

From the Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas 77030

We examined the kinetics of G_s and G_i regulation of human type V and type VI adenylyl cyclase (AC V and AC VI) in order to better model interactions between AC and its regulators. Activation of AC VI by G_s displayed classical Michaelis-Menten kinetics, whereas AC V activation by G_s was cooperative with a Hill coefficient of 1.4. The basal activity of human AC V, but not that of AC VI, was inhibited by G_i. Both enzymes showed greater inhibition by G_i at low G_s concentrations; however, human AC V was activated by G_i at high G_s concentrations. Neither regulator had an effect on the K_m for Mg-ATP. Mutations made within the G_s binding pocket of AC V (N1090D) and VI (F1078S) displayed 6- and 14-fold greater EC₅₀ values for G_s activation but had no effect on G_i inhibition of basal activity or K_m for Mg-ATP. G_s-stimulated AC VI-F1078S was not significantly inhibited by G_i, despite normal inhibition by G_i upon forskolin stimulation. Mechanistic models for G_s and G_i regulation of AC V and VI were derived to describe these results. Our models are consistent with previous studies, predicting a decrease in affinity of G_i in the presence of G_s. For AC VI, G_s is required for inhibition but not binding by G_i. For AC V, binding of two molecules of G_s and G_i to an AC dimer are required to fully describe the data. These models highlight the differences between AC V and VI and the complex interactions with two important regulators.

Received for publication, August 10, 2004 , and in revised form, November 10, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030. Tel.: 713-500-6308; Fax: 713-500-7444; E-mail: Carmen.W.Dessauer{at}uth.tmc.edu.

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