Neurotransmitters are stimulatory as well as inhibitory regulators of cell migration.
Angiotensin is such an inhibitory regulator of the SDF-1-induced migration of cytotoxic T lymphocytes, as we have investigated by time-lapse videomicroscopy and computer-assisted cell tracking. For
angiotensin II, the most effective form of
angiotensin for the inhibition of migration, two
G protein-coupled receptors are known, which both downregulate the activity of the
adenylyl cyclase via activation of inhibitory
G proteins. This downregulation of the enzymatic activity is a key signaling event for the inhibition of T lymphocyte and
tumor cell migration, while stimulatory
neurotransmitters--for example,
norepinephrine--cause an activation of the
adenylyl cyclase. Similar to
angiotensin, the SDF-1-induced migration of cytotoxic T lymphocytes was inhibited by
DAMGO, a specific agonist for the
mu-opioid receptor, which is coupled to inhibitory
G proteins, too. More interestingly,
DAMGO downregulated the
met-enkephalin-induced migration of MDA-MB-468
breast carcinoma cells.
Met-enkephalin binds to the
delta-opioid receptor and, with lower affinity, to the
mu-opioid receptor. Since the
delta-opioid receptor also activates inhibitory
G proteins, the promigratory effect of
met-enkephalin is caused by an intracellular signaling distinct from the engagement of each
opioid receptor alone. In summary, the dual control of the
adenylyl cyclase functions as an integrator of stimulatory and inhibitory signals for T lymphocyte and
tumor cell migration, which are delivered by
neurotransmitters and other signal substances that bind to
G protein-coupled receptors.