Signal transduction - cAMP signaling

cAMP Signaling

Adenylate cyclases (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 [1].

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 (PKC).

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 [2]. 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 Calcineurin [2].

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 [3]. 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) [4], Ryanodine receptor 1 (RYR1) [5], Lipase, hormone-sensitive (LIPS) [6], 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) [7].

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 [8], [9].

References:

1. Hanoune J, Defer N
   Regulation and role of adenylyl cyclase isoforms. Annual review of pharmacology and toxicology 2001;41:145-74
2. 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
3. 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
4. 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
5. 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
6. 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
7. Thomason P, Traynor D, Kay R
   Taking the plunge. Terminal differentiation in Dictyostelium. Trends in genetics : TIG 1999 Jan;15(1):15-9
8. 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
9. 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