Adenylate cyclase

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Epinephrine binds its receptor, that associates with an heterotrimeric G protein. The G protein associates with adenylate cyclase that converts ATP to cAMP, spreading the signal (more details...)

Overview

Adenylate cyclase (EC 4.6.1.1, also known as adenylyl cyclase or AC) is a lyase enzyme.

Types

There are ten known adenylate cyclases in mammals:

ADCY1
ADCY2
ADCY3
ADCY4
ADCY5
ADCY6
ADCY7
ADCY8
ADCY9
ADCY10

Reaction

Adenylate cyclase catalyzes the conversion of ATP to 3',5'-cyclic AMP (cAMP) and pyrophosphate.

cAMP is an important molecule in eukaryotic signal transduction, a so-called second messenger. Adenylate cyclase can be activated or inhibited by G proteins, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli. Following activation of adenylate cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels.

Photoactivatable adenylate cyclase (PAC) was discovered in E. gracilis and can be expressed in other organisms through genetic manipulation. Shining blue light on a cell containing PAC activates it and abruptly increases the rate of conversion of ATP to cAMP. This is a useful technique for researchers in neuroscience because it allows them to quickly increase the intracellular cAMP levels in particular neurons, and to study the effect of that increase in neural activity on the behavior of the organism. For example, PAC expression in certain neurons has been shown to alter the grooming behavior in fruit flies exposed to blue light [2]. Researchers also use channelrhodopsin-2 in a similar fashion.

Structure

Adenylyl cyclase is a transmembrane protein. It passes through the plasma membrane twelve times.

The important parts for its function are located in the cytoplasm and can be subdivided into the N-terminus, C1a, C1b, C2a and C2b.

The C1 region exists between transmembrane helices six and seven and the C2 region follows transmembrane helix 12.

The C1a and C2a domains form a catalytic dimer where ATP binds and is converted to cAMP.

Regulation

Adenylate cyclase is stimulated by G proteins, and by forskolin, as well as other class-specific substrates:

Isoforms I, III and VIII are also stimulated by Ca²⁺/calmodulin.
Isoforms V and VI are inhibited by Ca²⁺ in a calmodulin-independent manner.

In neurons, adenylate cyclases are located next to calcium ion channels for faster reaction to Ca²⁺ influx; they are suspected of playing an important role in learning processes. This is supported by the fact that adenylate cyclases are coincidence detectors, meaning that they are only activated by several different signals occurring together.