Review
G protein regulation of adenylate cyclase

https://doi.org/10.1016/S0165-6147(99)01307-3Get rights and content

Abstract

Adenylate cyclase integrates positive and negative signals that act through G protein-coupled cell-surface receptors with other extracellular stimuli to finely regulate levels of cAMP within the cell. Recently, the structures of the cyclase catalytic core complexed with the plant diterpene forskolin, and a cyclase–forskolin complex bound to an activated form of the stimulatory G protein subunit Gsα have been solved by X-ray crystallography. These structures provide a wealth of detail about how different signals could converge at the core cyclase domains to regulate catalysis. In this article, William Simonds reviews recent advances in the molecular and structural biology of this key regulatory enzyme, which provide new insight into its ability to integrate multiple signals in diverse cellular contexts.

Section snippets

Adenylate cyclase: a family of Gs-regulated isoenzymes

Isolation of the cDNA for the first AC (AC1) by Krupinski et al.5 was accomplished using sequence information from proteolytic peptides derived from affinity-purified brain AC. The cDNAs for AC1, along with the eight other AC isoforms subsequently isolated by probe cross-hybridization or PCR, encode large integral membrane proteins (Table 1). All are predicted by hydropathy analysis to share a common topology with five domains in sequence: a cytoplasmic N-terminal region, a membrane-anchoring

Inhibition of adenylate cyclase by Gα subunits of the Gi family

The complexity of hormonal control of adenylate cyclase was first evinced by Rodbell and co-workers, who demonstrated dual stimulatory and inhibitory G protein regulatory pathways4. In most settings, the inhibitory action of G protein-coupled receptors on AC activity can be blocked by treatment of cells with pertussis toxin (PTX), an exotoxin from Bordetella pertussis with ADP-ribosyltransferase activity. The recognition that a G protein was the major 41 kDa pertussis toxin substrate in many

Gβγ regulation of adenylate cyclase isoforms

The β and γ subunits of G proteins form a tight, irreversible heterodimer which functions as a single entity in the G protein cycle. It is now recognized that the Gβγ complex, though originally conceptualized as the passive, stabilizing binding partner for Gα subunits at the completion of a signalling cycle, carries an independent signal to many types of cellular effectors upon G protein activation54. Their direct role in AC regulation was unsuspected until the cloning of the first AC isoforms

Insights from adenylate cyclase crystal structures

The dramatic elucidation by Hurley and co-workers of a crystal structure of an AC2 C2 homodimer1 and the subsequent structural determination by Tesmer et al. of Gsα–GTPγ-S in complex with an AC5 C1–AC2 C2 heterodimer2 offer the first glimpses into the heart of the cyclase catalyst (Fig. 4). The Hurley group described an overall wreath-like structure consisting of two C2 domains packed head-to-tail into a dimer with extensive intermolecular interactions. On one side of the dimer (the ‘ventral’

Concluding remarks and future directions

The heterogeneity of AC isoforms allows for tissue and cell-specific responsiveness to particular extracellular signals, with integration of Gα and Gβγ subunits, or both, with signals from other sources affecting intracellular Ca2+ levels and PKC activity. A great step forward in understanding the mechanism of catalysis and regulation of AC has come with the recent three-dimensional structural determination of the cyclase catalytic core, and a complex of activated Gsα bound to a C1/C2

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