Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

doi:10.1016/j.jmb.2006.07.045

Journal of Molecular Biology

Volume 362, Issue 4, 29 September 2006, Pages 623-639

https://doi.org/10.1016/j.jmb.2006.07.045 Get rights and content

Abstract

The second messenger cAMP has been extensively studied for half a century, but the plethora of regulatory mechanisms controlling cAMP synthesis in mammalian cells is just beginning to be revealed. In mammalian cells, cAMP is produced by two evolutionary related families of adenylyl cyclases, soluble adenylyl cyclases (sAC) and transmembrane adenylyl cyclases (tmAC). These two enzyme families serve distinct physiological functions. They share a conserved overall architecture in their catalytic domains and a common catalytic mechanism, but they differ in their sub-cellular localizations and responses to various regulators. The major regulators of tmACs are heterotrimeric G proteins, which transduce extracellular signals via G protein-coupled receptors. sAC enzymes, in contrast, are regulated by the intracellular signaling molecules bicarbonate and calcium. Here, we discuss and compare the biochemical, structural and regulatory characteristics of the two mammalian AC families. This comparison reveals the mechanisms underlying their different properties but also illustrates many unifying themes for these evolutionary related signaling enzymes.

Introduction

The second messenger cyclic adenosine 3′,5′-monophosphate (cAMP) was discovered by Earl Sutherland during his studies of hormonal regulation of metabolism in mammalian heart and liver.¹^,² Subsequent studies revealed cAMP to be a prototypical second messenger, modulating physiological processes in all domains and kingdoms of life (its presence in plants remains controversial). The effects of cAMP are mediated by distinct targets in different kingdoms. In mammalian cells there are at least three known types of cAMP effector proteins: protein kinase A (PKA), exchange proteins activated by cAMP (EPACs), and cyclic nucleotide gated ion channels (CNGs and HCNs),³ plus a potential fourth target recently identified, Phosphodiesterase type 10.⁴ The second messenger is universally generated by adenylyl cyclases (AC; EC 4.6.1.1), enzymes that catalyze the cyclization of ATP to generate cAMP and inorganic pyrophosphate. Nucleotidyl cyclases (i.e. enzymes generating cAMP and the related second messenger cGMP from GTP) are a diverse family of enzymes that can be separated into six classes⁵^,⁶ (see below), with all known eukaryotic nucleotidyl cyclases belonging to a single class (class III). In many organisms and cell types, several different adenylyl cyclases (ACs) and/or guanylyl cyclases (GCs) are expressed simultaneously.⁷ Such heterogeneity reflects the multitude of cellular processes that are regulated by cyclic nucleotide second messengers in eukaryotic cells.

In mammals, cAMP is formed by either of two types of widely expressed Class III ACs (Figure 1). A family of transmembrane adenylyl cyclases (tmACs) encoded by nine distinct genes termed type I through type IX was discovered first, and this family represents the more widely studied source of cAMP. tmACs are directly regulated by heterotrimeric G proteins and generate cAMP in response to hormones and neurotransmitters which signal through G protein-coupled receptors (GPCRs).⁸ As their name implies, tmACs are obligatory membrane proteins. The individual regulatory properties of each isoform have been reviewed extensively,⁷^,⁹^,¹⁰ and specific tmAC isoforms have been linked to a subset of the physiological responses mediated by tmACs; for example, learning and memory,11., 12., 13., 14. cardiac myocyte function,¹⁵ and olfaction¹⁶ are, at least in part, mediated by tmACs types I and VIII, type V, and type III, respectively.

A second, independent source of cAMP in mammalian cells is the more recently discovered, soluble adenylyl cyclase (sAC).¹⁷ sAC is uniquely regulated by bicarbonate¹⁸ and calcium,¹⁹^,²⁰ and it is insensitive to heterotrimeric G protein regulation.¹⁷ sAC is widely expressed²¹ and is not strictly a soluble protein; it is present at discrete sub-cellular localizations in a wide variety of cells.²² Isoform diversity from the single confirmed sAC gene in mammalian genomes is generated by complex alternative splicing.²³^,²⁴ Physiological processes demonstrated to be regulated by sAC include sperm activation,²⁵^,²⁶ pH regulation in epididymis,²⁷ and TNF activation of granulocytes.²⁸ Its unique regulation by bicarbonate suggests it also contributes to other processes responsive to carbon dioxide and/or functions as a metabolic sensor in cells.²⁹

The catalytic mechanisms and regulation of both mammalian G protein-regulated tmAC catalytic domains and a bicarbonate-regulated, bacterial sAC-like cyclase has now been studied kinetically and crystallographically. Here, we discuss the biochemical, structural and regulatory characteristics of these two families of mammalian ACs. This comparison reveals the mechanisms underlying their different properties and illustrates many unifying themes for these evolutionary related signaling enzymes.

Section snippets

Classification of Nucleotidyl Cyclases

The known nucleotidyl cyclase sequences have been grouped into six classes based on sequence homology within their catalytic portions.⁵^,⁶ The AC enzymes from Escherichia coli and a number of related Gram-negative prokaryotes belong to class I. Class II is comprised of the “toxin” ACs from pathogens such as Bordetella pertussis³⁰ and Bacillus anthracis.³¹ These ACs are secreted enzymes that translocate into host cells where they disrupt intracellular signaling by flooding host cells with

Evolution of Mammalian Adenylyl Cyclases

sAC appears to be the most ancient among mammalian cyclases; its sequence is more similar to ACs from cyanobacteria and myxobacteria than to other mammalian cyclases¹⁷ (Figure 3). Additionally, mammalian sAC and the CyaC cyclase from the cyanobacteria Spirulina platensis are similarly regulated; both are synergistically activated by bicarbonate and calcium ions.²⁰^,⁴² Bicarbonate-regulated sAC-like cyclases are also found in Anabaena PCC 7120, Stigmatella aurantiaca, Mycobacterium tuberculosis,⁴³

Molecular Structure

As stated above, the functional catalytic unit of class III enzymes is formed by either homodimerization of a single catalytic domain or heterodimerization of structurally similar C₁ and C₂ catalytic domain monomers. The first crystal structure of a class III AC catalytic domain to be solved was a non-physiological mammalian C₂ homodimer,⁵³ followed by crystal structures of a mammalian C₁C₂ heterodimer,⁴⁰^,⁵⁴ two trypanosomal catalytic cores,⁵⁵ several mycobacterial ACs,⁴¹^,⁵⁶^,⁵⁷ and a

The Catalytic Mechanism of Class III Cyclases

The overall structure as well as most residues involved in substrate binding and catalysis are conserved among class III cyclases. The positions with variations mostly show functionally conserved substitutions (see above) which define a limited number of subfamilies within class III.³² Therefore, it is likely that class III cyclases share a common catalytic mechanism. The small differences between individual cyclases or subfamilies, such as the Δ-loop in trypanosomal ACs,⁵⁵ mostly confer unique

Regulation of Adenylyl Cyclases

In mammals, cAMP is involved in a multitude of physiological processes.⁹ In fact, this single second messenger can modulate seemingly disparate functions within a single cell.⁶⁹^,⁷⁰ The co-existence of sAC and tmACs, along with a broad family of cAMP degrading phosphodiesterases (PDEs),⁷¹ permitted a revision of the original models for cAMP signal transduction in order to explain this paradox. These original models relied upon diffusion through the cytoplasm of the second messenger generated at

Isoform Diversity

In mammals, nine genes encode tmACs. These are numbered AC I through IX, according to their time of discovery, and each displays unique regulatory properties.⁷^,⁹^,¹⁰^,⁷⁷ Besides the different tissue distribution of these isoforms, there are also reports of alternative splicing of some of the tmAC genes, increasing their isoform complexity. Three tmAC VIII variants were identified in rat brain.⁷⁸ In addition to a “full-length” isoform, one isoform is missing potential glycosylation sites from an

Protein Regulators

The major regulators of tmACs are heterotrimeric G-proteins. The α-subunit of G_s (G_sα) stimulates most if not all the tmAC isoforms. In contrast, G_iα selectively inhibits tmACs I, V, and VI, and individual tmAC isoforms also display unique regulation by G protein βγ subunits.⁷^,¹⁰ Despite their structural similarities (described above), the three-dimensional structures reveal differences that might explain sAC's insensitivity to heterotrimeric G-protein regulation. A region implicated in Gβγ

Forskolin

Forskolin is a diterpene compound isolated from plants that activates all mammalian tmACs¹⁰^,¹⁰⁹ with the exception of tmAC IX.¹¹⁰^,¹¹¹ It occupies part of the second, degenerated “active site” in tmACs (Figure 4(a)),⁴⁰ and it has been speculated to exploit the binding site of an as yet unidentified endogenous regulatory ligand. Forskolin has been suggested to activate tmACs by inducing dimerization and/or active site rearrangements,⁴⁰ but this idea remains speculative because the structure of a

Concluding Remarks

Even though cAMP has been extensively studied for over 50 years, the plethora of regulatory mechanisms controlling cAMP synthesis is just beginning to be uncovered. In mammalian cells this important second messenger can be produced by two related families of adenylyl cyclases, sAC and tmACs. These enzymes share a conserved catalytic mechanism but differ in their specific physiological functions due to altered regulation and distinct intracellular localization. Additional modes of regulation

Acknowledgements

We gratefully acknowledge Melanie Gertz and Drs Martin Cann, Joachim Schultz, and Wei-Jen Tang for critical reading of the manuscript and valuable suggestions. We thank Lucy Skrabanek for assistance with generating the phylogenetic tree. Recent work from the authors laboratories described in this review has been funded by the Ellison Medical Foundation (to J.B.), American Diabetes Association (to L.R.L.), Hirschl-Weil Cauler Trust (to L.R.L.), National Institutes of Health (AI64842, GM62328,

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Journal of Molecular Biology

ReviewMolecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

Abstract

Introduction

Section snippets

Classification of Nucleotidyl Cyclases

Evolution of Mammalian Adenylyl Cyclases

Molecular Structure

The Catalytic Mechanism of Class III Cyclases

Regulation of Adenylyl Cyclases

Isoform Diversity

Protein Regulators

Forskolin

Concluding Remarks

Acknowledgements

J. Biol. Chem.

J. Biol. Chem.

FEBS Letters

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

Neuron

J. Biol. Chem.

J. Biol. Chem.

Dev. Cell

J. Biol. Chem.

Trends Endocrinol. Metab.

Trends Microbiol.

Cell Signal.

FEMS Microbiol. Letters

J. Biol. Chem.

J. Biol. Chem.

Gene

J. Biol. Chem.

Cell Signal.

Curr. Biol.

J. Mol. Biol.

J. Biol. Chem.

J. Biol. Chem.

Curr. Opin. Struct. Biol.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Curr. Opin. Cell Biol.

J. Biol. Chem.

Mol. Cell Endocrinol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Phylogeny of adenylyl cyclases

Adv. Second Messenger Phosphoprotein Res.

The Rhizobium etli cyaC product: characterization of a novel adenylate cyclase class

J. Bacteriol.

Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase

Am. J. Physiol. Renal Physiol.

Regulation and role of adenylyl cyclase isoforms

Annu. Rev. Pharmacol.Toxicol.

Isoforms of mammalian adenylyl cyclase: multiplicities of signaling

Mol. Interv.

Type 8 adenylyl cyclase is targeted to excitatory synapses and required for mossy fiber long-term potentiation

J. Neurosci.

Altered behavior and long-term potentiation in type I adenylyl cyclase mutant mice

Proc. Natl Acad. Sci. USA

Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy

Biochem. Soc. Trans.

Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals

Proc. Natl Acad. Sci. USA

Review
Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems