Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

ADCY8 (P40145) - Overview - Molecular Target Synopsis

Protein


ADCY8, Adenylate cyclase type 8
Enzyme Classification 4.6.1.1
UniProt P40145

Also Known as ADCY8_HUMAN, ADCY8

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. Homodimer; via transmembrane domain. Monomer. Heterodimer. Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation. Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft. Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events. Interacts with STIM1. Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8. Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent. Interacts with PPP2R5D.

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: ADCY8 is active in the following subcellular-locations: apical cell membrane, axon, basolateral cell membrane, caveola, cell junction, cell membrane, cell projection, clathrin-coated vesicle membrane, coated pit, cytoplasmic vesicle, dendrite, membrane, membrane raft, postsynaptic cell membrane, postsynaptic density, presynaptic cell membrane, synapse.
GO terms: ADCY8 is active in the following subcellular-locations: apical plasma membrane, axon, basolateral plasma membrane, caveola, cell junction, clathrin-coated pit, clathrin-coated vesicle membrane, dendrite, excitatory synapse, glutamatergic synapse, hippocampal mossy fiber to CA3 synapse, integral component of plasma membrane, integral component of presynaptic membrane, membrane, membrane raft, neuronal cell body membrane, plasma membrane, plasma membrane raft, postsynaptic density, postsynaptic membrane, presynaptic active zone, Schaffer collateral - CA1 synapse.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project ADCY8 has gain in 35 cell-lines, loss in 1 cell-lines and no signal in 969 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: MCF7, SK_OV_3, MOLT_4

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H920, NCI-H727, NCI-H1930

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, NHLF, HSMM

(see details)

3D Structures


At greater than 50% identity similarity to ADCY8 there are:
17 structures (34 chains) solved
17 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


ADCY8 has been screened with 49 compounds (52 bioactivities), 23 compounds have bioactivities that show binding affinity of <= 500nM (24 bioactivities). (see details)