Аннотация
Neuropeptides like galanin produced and released by small cell lung
cancer (SCLC) cells are considered principal mitogens in these tumors.
We identified the galanin receptor type 2 (GALR2) as the only galanin
receptor expressed in H69 and H510 cells. Photoaffinity labeling
of G proteins in H69 cell membranes revealed that GALR2 activates
G proteins of three subfamilies: G(q), G(i), and G(12). In H69 cells,
galanin-induced Ca2+ mobilization was pertussis toxin-insensitive.
While phorbol ester-induced extracellular signal-regulated kinase
(ERK) activation required protein kinase C (PKC) activity, preincubation
of H69 cells with the PKC-inhibitor GF109203X had no effect on galanin-dependent
ERK activity. A rise of the intracellular calcium concentration was
necessary and sufficient to mediate galanin-induced ERK activation.
In support of G(i) coupling, stimulation of GALR2 expressed in HEK293
cells inhibited isoproterenol-induced cAMP accumulation and raised
cAMP levels in COS-7 cells when coexpressed with a chimeric G alpha(S)-G
alpha(i) protein In H69 cells, galanin activated the monomeric GTPase
RhoA and induced stress fiber formation in Swiss 3T3 cells expressing
GALR2. Thus, we provide the first direct evidence that in SCLC the
mitogenic neuropeptide galanin, interacting with GALR2, simultaneously
activates multiple classes of G proteins and signals through the
G(q) phospholipase C/calcium sequence and a G(12)/Rho pathway. Oncogene
(2000) 19, 4199 - 4209
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