ADCY8
Domain
The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly. The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8.
Function
Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion. Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation. Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment. Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells.
Post-translational modifications
Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8.
N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity.
Sequence Similarities
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
Tissue Specificity
Detected in brain cortex (PubMed:1715695). Expressed in islet (PubMed:25403481).
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Basolateral cell membrane
- Apical cell membrane
- Synapse
- Cell projection
- Dendrite
- Cell projection
- Axon
- Presynaptic cell membrane
- Postsynaptic density
- Membrane raft
- Membrane
- Coated pit
- Cytoplasmic vesicle
- Clathrin-coated vesicle membrane
- Membrane
- Caveola
- Localized to dendritic arbors (By similarity). Monomeric N-glycosylated species localizes in membrane raft. In contrast, monomeric unglycosylated forms are enriched in clathrin-coated pits and vesicles. Dimers are also localized outside of membrane rafts. Membrane raft localization and integrity is indispensable for CCE-stimulated adenylate cyclase activity (By similarity).
Alternative names
Adenylate cyclase type 8, ATP pyrophosphate-lyase 8, Adenylate cyclase type VIII, Adenylyl cyclase 8, Ca(2+)/calmodulin-activated adenylyl cyclase, AC8, ADCY8