(ACs) are a
family of enzymes that produce cyclic AMP (cAMP) from ATP
upon extracellular stimulation. To date, at least 9 membrane-bound
ACs have been isolated and characterized. Intracellular
signaling via cAMP generates downstream effects that range
from changes in the function of ion channels to changes in intracellular energy
metabolism and gene transcription .
Adenylate cyclases are capable of integrating positive
and negative signals that act directly from G protein-coupled receptors
(GPCRs) through stimulation of the G-protein
alpha and beta/gamma subunits or indirectly
via intracellular signaling by protein kinases: Protein kinase A
(PKA), Calcium/calmodulin-dependent protein kinase
(CaMK), and Protein kinase C
Stimulation through G-protein alpha-s is the major
mechanism, by which ACs are activated and
cAMP levels are elevated. Whereas all isoforms of
ACs are potentially activated by G-protein
alpha-s -coupled receptors, the inhibition by G-protein
alpha-i family-coupled receptors appears to be isozyme specific.
G-protein alpha-i family acts as a noncompetitive inhibitor
of G-protein alpha-s -stimulated Adenylate cyclases 1, 5 and
6 (Adenylate cyclase type I, Adenylate cyclase
type V and Adenylate cyclase type VI), and
decreases level of cAMP .
G-proteins beta/gamma subunits stimulate Adenylate cyclases
2, 4 and 7 (Adenylate cyclase type II,
Adenylate cyclase type IV and Adenylate
cyclase type VII) and inhibit Adenylate cyclase type
I, Adenylate cyclase type V and
Adenylate cyclase type VI.
Adenylate cyclases type I, II, III, V, VI and VII have
been shown to be directly phosphorylated by PKC isoenzymes.
Adenylate cyclase type V is phosphorylated and activated by
Protein kinase C alpha and zeta (PKC-alpha,
PKC-zeta); Adenylate cyclase type II - by
PKC-alpha; Adenylate cyclase type
VII - by Protein kinase C delta (PKC-delta).
Adenylate cyclase type VI is phosphorylated and inhibited by
PKC. Adenylate cyclases type I
is phosphorylated and inhibited by Calcium/calmodulin-dependent protein kinase IV
(CaMK IV), Adenylate cyclases type
III is phosphorylated and inhibited by Calcium/calmodulin-dependent
protein kinase (CaM kinase) II (CaMK II).
Adenylate cyclases type IX is indirectly inhibited by
Ca('2+) via the activation of
PKA is a significant target of cAMP.
PKA consist of Protein kinase, cAMP-dependent, regulatory
(PKA-reg (cAMP-dependent)) and catalytic
(PKA-cat (cAMP-dependent)) subunits. PKA-reg
(cAMP-dependent bind and inhibit the PKA-cat
(cAMP-dependent). cAMP molecules bind to each
regulatory subunit, eliciting a reversible conformational change that releases active
catalytic subunits . PKA directly
phosphorylates and inhibits Adenylate cyclases type V and
IV, realizing feedback regulation.
PKA also phosphorylates and stimulates cAMP responsive
element binding protein 1 (CREB1) ,
Ryanodine receptor 1 (RYR1) , Lipase,
hormone-sensitive (LIPS) , Phosphorylase
kinase, alpha (PHK alpha),
Phospholamban, KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum
protein retention receptors (KDELR), and inhibits Glycogen
synthase kinase-alpha/beta (GSK3alpha/beta) .
Other targets for cAMP are guanine nucleotide exchange
factors (GEFs) that modulate activity of small GTPases. cAMP
binding to Rap guanine nucleotide exchange factors (GEF) 3 and 4
(cAMP-GEFI and cAMP-GEFII)
activate RAP1A and RAP2A, members of RAS oncogene family (RAP-1A
and RAP-2A) pathways, respectively , .
- Hanoune J, Defer N
Regulation and role of adenylyl cyclase isoforms.
Annual review of pharmacology and toxicology 2001;41:145-74
- Defer N, Best-Belpomme M, Hanoune J
Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase.
American journal of physiology. Renal physiology 2000 Sep;279(3):F400-16
- Herberg FW, Maleszka A, Eide T, Vossebein L, Tasken K
Analysis of A-kinase anchoring protein (AKAP) interaction with protein kinase A (PKA) regulatory subunits: PKA isoform specificity in AKAP binding.
Journal of molecular biology 2000 Apr 28;298(2):329-39
- Don J, Stelzer G
The expanding family of CREB/CREM transcription factors that are involved with spermatogenesis.
Molecular and cellular endocrinology 2002 Feb 22;187(1-2):115-24
- Yano M, Kobayashi S, Kohno M, Doi M, Tokuhisa T, Okuda S, Suetsugu M, Hisaoka T, Obayashi M, Ohkusa T, Kohno M, Matsuzaki M
FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure.
Circulation 2003 Jan 28;107(3):477-84
- Maehira F, Zaha F, Miyagi I, Tanahara A, Noho A
Effects of passive smoking on the regulation of rat aortic cholesteryl ester hydrolases by signal transduction.
Lipids 2000 May;35(5):503-11
- Thomason P, Traynor D, Kay R
Taking the plunge. Terminal differentiation in Dictyostelium.
Trends in genetics : TIG 1999 Jan;15(1):15-9
- Vanvooren V, Allgeier A, Nguyen M, Massart C, Parma J, Dumont JE, Van Sande J
Mutation analysis of the Epac--Rap1 signaling pathway in cold thyroid follicular adenomas.
European journal of endocrinology / European Federation of Endocrine Societies 2001 Jun;144(6):605-10
- Fujita T, Meguro T, Fukuyama R, Nakamuta H, Koida M
New signaling pathway for parathyroid hormone and cyclic AMP action on extracellular-regulated kinase and cell proliferation in bone cells. Checkpoint of modulation by cyclic AMP.
The Journal of biological chemistry 2002 Jun 21;277(25):22191-200