Why Calcium-Stimulated Adenylyl Cyclases?

Abstract

(C1), another six-transmembrane domain (M2), and a cytoplasmic carboxy terminus of ~35 kDa (C2) (FIGURE 1B). The catalytic domain of adenylyl cyclases is hypothesized to be bipartite and split between C1 and C2 regions. The predicted size of mammalian adenylyl cyclases ranges from 110 to 130 kDa, but these proteins generally have an apparent molecular weight on SDS gels of ~200 kDa due to glycosylation in the extracellular loops of M1 and M2. Although the membrane topology and structure of adenylyl cyclases resemble transporters and ion channels, there is no evidence that these enzymes function as transporters or ion channels. However, cultured neurons express a voltage-sensitive adenylyl cyclase activity (25), suggesting that neurons contain an adenylyl cyclase or regulatory protein that is, like some ion channels, sensitive to membrane potential. AC1 is a Neurospecific Coincidence DetectorAC1 is the only neurospecific adenylyl cyclase identified thus far. It is expressed in brain, retina, and the adrenal medulla (45). Within the brain, AC1 is expressed in the hippocampus, neocortex, entorhinal cortex, cerebellar cortex, olfactory bulb, and pineal gland (29,45). AC1 expression in hippocampus increases dramatically during postnatal days 1-16 (31). The tissue specificity and developmentally regulated expression of the AC1 gene may be controlled by a 280-bp region and binary E-box like factor just 5Ј to the transcriptional start site (5). AC1 protein is detectable in the mossy fibers and the molecular layer of hippocampus and dentate in the macaque monkey, Macaca nemestrina (13), suggesting that AC1 is localized to axons in neurons of the hippocampus.Ca 2+ and CaM stimulate AC1 enzymatic activity with a half-maximal concentration of 150 nM free Ca 2+ , slightly above resting concentrations of Ca 2+ in neurons (43). CaM interacts with AC1 within the C1 loop region, close to the catalytic domain (43). The CaM-binding site within this region was identified by using peptide competitors and site-specifAdenylyl cyclases catalyze the conversion of ATP to cAMP, an important second messenger with diverse regulatory roles in the nervous system. Ten members of the adenylyl cyclase family have been identified by isolation of specific clones, each with unique regulatory properties and tissue distribution (for review see Ref. 46). In the brain, as in other tissues, adenylyl cyclases can be activated by receptor-coupled stimulatory G s proteins. For example, noradrenergic neurons of the locus ceruleus project to pyramidal neurons of the hippocampus and activate adenylyl cyclase through G s protein-coupled ␤-adrenergic receptors (FIGURE 1). Two of the adenylyl cyclases, AC1 and AC8, are activated by Ca 2+ through the Ca 2+ -binding protein calmodulin (CaM). This review focuses on the CaM-stimulated adenylyl cyclases and their role in neuronal signaling, synaptic plasticity, and memory formation. These enzymes link activitydependent increases in intracellular Ca 2+ to the production of intracellular cAMP. Isolation and Structure o...

cAMP-PKA phosphorylation of tau confers risk for degeneration in aging association cortex

“…cAMP production (18), fueling feedforward signaling (14). Ca 2+ -cAMP-PKA signaling increases the open state of nearby K + channels (SK, HCN, KCNQ) on the spine membrane, which temporarily weakens synaptic efficacy, thus providing dynamic gating of network inputs to enhance mental flexibility and coordinate cognitive and arousal states (14) (see Fig.…”

Distinct regional and subcellular localization of adenylyl cyclases type 1 and 8 in mouse brain

“…Known AC isoforms share general structural organization as predicted by hydropathy and sequence analysis, including a short cytoplasmic amino terminus, two sixtransmembrane domains, a 40-kD cytoplasmic loop and a cytoplasmic carboxy terminus of about 35 kD (Ferguson and Storm, 2004). Despite similarities in their structural composition, the ten identified mammalian AC isoforms differ in their functional characteristics (Cooper, 2003), reflecting the diversity among cAMP-dependent mechanisms.…”

Differential cAMP Signaling at Hippocampal Output Synapses

“…Two of the eight known forms of adenylyl cyclase (AC) are activated by calcium, AC1 and AC8 (for review, see Ferguson and Storm, 2004). High levels of AC1 and AC8 mRNA are found in the hippocampus, the dentate gyrus, area CA3, and area CA1 (Xia et al, 1991;Mons et al, 1995).…”

“…cAMP is an important second messenger and its crucial role in learning and memory has been provided by many genetic and pharmacological studies (for review, see Nguyen and Woo, 2003;Ferguson and Storm, 2004). Genetic inactivation of the cAMP signaling pathway results in learning and memory impairment (Wu et al, 1995;Wong et al, 1999), whereas transgenic mice with increased cAMP levels show improved memory (Wang et al, 2004).…”