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From the School of Biological Sciences, University of East Anglia, Norwich, United Kingdom.
PURPOSE. To investigate regional differences in Ca2+ mobilization kinetics in the intact human lens produced by exposure to agonists of tyrosine-kinase and G-protein–coupled receptors and to characterize the major receptor subtypes involved in Ca2+ signaling in the different regions.
METHODS. Whole human lenses were placed anterior side down in a plastic chamber and perifused with artificial aqueous humor (AAH) at 30°C. After fura-2 incorporation, cytosolic Ca2+ levels were monitored by using epifluorescence techniques in either the equatorial or central anterior epithelial cells of the intact lens. Agonists dissolved in AAH were applied to the lens in successive short pulses.
RESULTS. Central anterior lens epithelial cells produced a large response to 10
µM acetylcholine (ACh) and histamine; only a small response to
adenosine triphosphate (ATP); and no response to 10 µM adrenalin, 10
ng/ml epithelial growth factor (EGF) or TGF
, or 50 ng/ml
platelet-derived growth factor (PDGF)-AB. Conversely, the equatorial
cells produced a strong response to 10 µM ATP and histamine, 10 ng/ml
EGF (or TGF), and 50 ng/ml PDGF-AB, but failed to respond to 10 µM
ACh or 10 µM adrenalin. The EGF-induced response in the equatorial
cells was blocked completely by tyrphostin (AG1478), a specific
inhibitor of the EGF receptor tyrosine kinase. Carbachol, a
nonhydrolyzable analogue of ACh, and pilocarpine, the M1 muscarinic
receptor–specific agonist, both produced the same trend of response
amplitude elicited by ACh in each region of the lens. The potency order
of purinergic agonist-induced Ca2+ mobilization at the
equator was consistent with the P2Y2 receptor subtype. The
histamine-induced response was abolished by 10 µM triprolidine, a
specific H1 receptor antagonist, but remained unaffected by
the specific H2 and H3 antagonists, ranitidine
and thioperamide, respectively.
CONCLUSIONS. There is a spatial heterogeneity in functional receptor activity in different regions of the whole lens. The important growth factor receptors for EGF and PDGF are functionally active only in the equatorial cells of the mature human lens. This study further shows that the ACh, histamine, and ATP-induced responses arise from the activation of M1 muscarinic, H1 histamine, and P2Y2 purinergic receptors, respectively.
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