Subtype alpha-1 adrenergic receptors consists of Alpha-1A adrenergic receptor, Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor. They participate in many physiological processes via different pathways. One of the best studied alpha-1 adrenergic receptors-stimulated pathways is a Mitogen-activated protein kinase 1 and 3 (ERK1/2) activation [1], [2].

Natural catecholamines, Adrenaline, and Noradrenaline, activate alpha-1 adrenergic receptors [1], [3]. The activated receptors interact with different Guanine nucleotide binding proteins (G-proteins). All three receptors interact with G-protein alpha-q and G-protein alpha-11 [4]. Alpha-1A adrenergic receptor and Alpha-1B adrenergic receptor couple with G-protein alpha-14 [5]. Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor interact with Transglutaminase 2 (TGM2) [6], [7], [8]. Alpha-1B adrenergic receptor couples with G-protein alpha-15 [5] and G-protein alpha activating activity polypeptide O (G-protein alpha-o) [4].

G-protein alpha-11, G-protein alpha-q, G-protein alpha-14, G-protein alpha-15 activate Phospholipase C beta 1 (PLC-beta1) [1], [5], [9]. TGM2 activate Phospholipase C delta 1 (PLC-delta1) [8], [10]. PLC-beta1 and PLC-delta1 hydrolyze Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to produce Inositol 1,4,5-trisphosphate (IP3) and 1,2-diacyl-glycerol (DAG) [8], [11].

DAG and IP3 participate in activation of Ca('2+)-dependent Protein kinase C alpha (PKC-alpha) [12], Ca('2+)-independent Protein kinases C delta and epsilon (PKC-delta and PKC-epsilon) [1], [13], [14] and mobilization of intracellular Ca('2+). All these pathways may lead to activation of cell growth and proliferation.

Cytosolic Ca('2+) activates Calmodulin / Calcium/calmodulin-dependent protein kinase II (CaMK II)/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2))/ v-src sarcoma viral oncogene homolog (c-Src)/ SHC transforming protein (Shc)/ Son of sevenless homolog (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) / v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) / Mitogen-activated protein kinase kinases 1 and 2 ((MEK1(MAP2K1) and MEK2(MAP2K2))/ Mitogen-activated protein kinase 1 and 3 (ERK1/2) pathway [13], [15].

G-protein alpha-q-stimulated PKC-alpha and PKC-epsilon may activate Erk cascade in H-Ras-independent manner (e.g., via phosphorylation of c-Raf-1) [16], [17]. On the other hand PKC-delta and PKC-epsilon may activate Erk cascade in H-Ras-independent manner via phosphorylation of Pyk2(FAK2) [16], [18], [19].

Alpha-1 adrenergic receptors-dependent ERK1/2 activation may also be realized via Phosphoinositide-3-kinase (PI3K) [20], [21]. c-Src can activate PI3K reg class IA (p85-alpha)/ PI3K cat class IA (p110-beta) directly [21], [22], [23] or via SHC transforming protein (Shc)/ Son of sevenless homolog (SOS)/ H-Ras [21].

Activated PI3K catalyzes transformation of PtdIns(4,5)P2 into Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Presumably, then PtdIns(3,4,5)P3 activates Shc / SOS / H-Ras. After that, H-Ras activates c-Raf-1 / MEK1(MAP2K1), MEK2(MAP2K2))/ ERK1/2 [15], [20], [21].

Activated ERK1/2 phosphorylate V-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) and Jun oncogene (c-Jun), thus activating cell growth and proliferation [1], [13], [21].

Moreover, PKC-alpha, probably phosphorylates Ca2+ channels (for example, Calcium channel, voltage-dependent L type (L-type Ca(II) channel) [24], [25]) and this increase extracellular Ca('2+) entry [26]. High level of Ca('2+) influence cell contraction [2]. Also, high level of Ca('2+), which was achieved due Ca2+ channels activation, may facilitate activation of Ca('2+) -dependent PKC-alpha, thus creating a positive feedback loop. CaMK II may activates L-type Ca(II) channel as well[27].

1. Garcia-Sainz JA, Vazquez-Prado J, Villalobos-Molina R
   Alpha 1-adrenoceptors: subtypes, signaling, and roles in health and disease. Archives of medical research 1999 Nov-Dec;30(6):449-58
2. Hague C, Gonzalez-Cabrera PJ, Jeffries WB, Abel PW
   Relationship between alpha(1)-adrenergic receptor-induced contraction and extracellular signal-regulated kinase activation in the bovine inferior alveolar artery. The Journal of pharmacology and experimental therapeutics 2002 Oct;303(1):403-11
3. Piascik MT, Perez DM
   Alpha1-adrenergic receptors: new insights and directions. The Journal of pharmacology and experimental therapeutics 2001 Aug;298(2):403-10
4. Gurdal H, Seasholtz TM, Wang HY, Brown RD, Johnson MD, Friedman E
   Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Molecular pharmacology 1997 Dec;52(6):1064-70
5. Wu D, Katz A, Lee CH, Simon MI
   Activation of phospholipase C by alpha 1-adrenergic receptors is mediated by the alpha subunits of Gq family. The Journal of biological chemistry 1992 Dec 25;267(36):25798-802
6. Baek KJ, Das T, Gray C, Antar S, Murugesan G, Im MJ
   Evidence that the Gh protein is a signal mediator from alpha 1-adrenoceptor to a phospholipase C. I. Identification of alpha 1-adrenoceptor-coupled Gh family and purification of Gh7 from bovine heart. The Journal of biological chemistry 1993 Dec 25;268(36):27390-7
7. Chen S, Lin F, Iismaa S, Lee KN, Birckbichler PJ, Graham RM
   Alpha1-adrenergic receptor signaling via Gh is subtype specific and independent of its transglutaminase activity. The Journal of biological chemistry 1996 Dec 13;271(50):32385-91
8. Kang SK, Kim DK, Damron DS, Baek KJ, Im MJ
   Modulation of intracellular Ca(2+) via alpha(1B)-adrenoreceptor signaling molecules, G alpha(h) (transglutaminase II) and phospholipase C-delta 1. Biochemical and biophysical research communications 2002 Apr 26;293(1):383-90
9. Lo RK, Cheung H, Wong YH
   Constitutively active Galpha16 stimulates STAT3 via a c-Src/JAK- and ERK-dependent mechanism. The Journal of biological chemistry 2003 Dec 26;278(52):52154-65
10. Zhang J, Tucholski J, Lesort M, Jope RS, Johnson GV
    Novel bimodal effects of the G-protein tissue transglutaminase on adrenoreceptor signalling. The Biochemical journal 1999 Nov 1;343 Pt 3:541-9
11. Arthur JF, Matkovich SJ, Mitchell CJ, Biden TJ, Woodcock EA
    Evidence for selective coupling of alpha 1-adrenergic receptors to phospholipase C-beta 1 in rat neonatal cardiomyocytes. The Journal of biological chemistry 2001 Oct 5;276(40):37341-6
12. Zhong H, Minneman KP
    Alpha1-adrenoceptor subtypes. European journal of pharmacology 1999 Jun 30;375(1-3):261-76
13. Hu ZW, Shi XY, Lin RZ, Chen J, Hoffman BB
    alpha1-Adrenergic receptor stimulation of mitogenesis in human vascular smooth muscle cells: role of tyrosine protein kinases and calcium in activation of mitogen-activated protein kinase. The Journal of pharmacology and experimental therapeutics 1999 Jul;290(1):28-37
14. Rohde S, Sabri A, Kamasamudran R, Steinberg SF
    The alpha(1)-adrenoceptor subtype- and protein kinase C isoform-dependence of Norepinephrine's actions in cardiomyocytes. Journal of molecular and cellular cardiology 2000 Jul;32(7):1193-209
15. Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ
    Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. The Journal of biological chemistry 1997 Aug 1;272(31):19125-32
16. Hawes BE, van Biesen T, Koch WJ, Luttrell LM, Lefkowitz RJ
    Distinct pathways of Gi- and Gq-mediated mitogen-activated protein kinase activation. The Journal of biological chemistry 1995 Jul 21;270(29):17148-53
17. Hamilton M, Liao J, Cathcart MK, Wolfman A
    Constitutive association of c-N-Ras with c-Raf-1 and protein kinase C epsilon in latent signaling modules. The Journal of biological chemistry 2001 Aug 3;276(31):29079-90
18. Ueda Y, Hirai S, Osada S, Suzuki A, Mizuno K, Ohno S
    Protein kinase C activates the MEK-ERK pathway in a manner independent of Ras and dependent on Raf. The Journal of biological chemistry 1996 Sep 20;271(38):23512-9
19. Bayer AL, Heidkamp MC, Howes AL, Heller Brown J, Byron KL, Samarel AM
    Protein kinase C epsilon-dependent activation of proline-rich tyrosine kinase 2 in neonatal rat ventricular myocytes. Journal of molecular and cellular cardiology 2003 Sep;35(9):1121-33
20. Hu ZW, Shi XY, Lin RZ, Hoffman BB
    Alpha1 adrenergic receptors activate phosphatidylinositol 3-kinase in human vascular smooth muscle cells. Role in mitogenesis. The Journal of biological chemistry 1996 Apr 12;271(15):8977-82
21. Hu ZW, Shi XY, Lin RZ, Hoffman BB
    Contrasting signaling pathways of alpha1A- and alpha1B-adrenergic receptor subtype activation of phosphatidylinositol 3-kinase and Ras in transfected NIH3T3 cells. Molecular endocrinology (Baltimore, Md.) 1999 Jan;13(1):3-14
22. Gentili C, Morelli S, Russo De Boland A
    Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes. Journal of cellular biochemistry 2002;86(4):773-83
23. Kubo H, Hazeki K, Takasuga S, Hazeki O
    Specific role for p85/p110beta in GTP-binding-protein-mediated activation of Akt. The Biochemical journal 2005 Dec 15;392(Pt 3):607-14
24. Liu SJ, Kennedy RH
    alpha1-Adrenergic activation of L-type Ca current in rat ventricular myocytes: perforated patch-clamp recordings. The American journal of physiology 1998 Jun;274(6 Pt 2):H2203-7
25. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
26. Graham RM, Perez DM, Hwa J, Piascik MT
    alpha 1-adrenergic receptor subtypes. Molecular structure, function, and signaling. Circulation research 1996 May;78(5):737-49
27. O-Uchi J, Komukai K, Kusakari Y, Obata T, Hongo K, Sasaki H, Kurihara S
    alpha1-adrenoceptor stimulation potentiates L-type Ca2+ current through Ca2+/calmodulin-dependent PK II (CaMKII) activation in rat ventricular myocytes. Proceedings of the National Academy of Sciences of the United States of America 2005 Jun 28;102(26):9400-5