Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia
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ABSTRACT |
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Voltage-gated
K+ currents in rat somatotrophs
are increased by somatostatin (SRIF) through unidentified G protein. In
this experiment, somatotroph-enriched cells (up to 85%) were obtained from ovine pituitary glands and further identified by the increase in
K+ currents by SRIF. The whole
cell recording was employed to study the voltage-gated
K+ currents. A reversible increase
in K+ currents (up to 150% of
control) was obtained in response to local application of SRIF (10 nM)
but not vehicle. When the guanosine 5'-O-(3-thiotriphosphate) was
included in the pipette solution (200 µM), the recovery phase of
K+ current response to SRIF was
abolished. Inclusion of guanosine 5'-O-(2-thiodiphosphate) (200 µM) in pipette solution blocked the
K+ current response to SRIF.
Intracellular dialysis of antibodies against
o-,
i-,
i-1-2-, or
i-3-subunits of G proteins via
patch pipettes was confirmed by immunofluorescent staining of the
antibodies. Antibody dialysis alone did not modify voltage-gated K+ currents. Dialysis of
anti-
i or
anti-
i-3 antibodies
significantly attenuated the increase in
K+ currents that was obtained
after application of 10 or 100 nM SRIF. Dialysis with
anti-
o,
anti-
i-1-2, or
heat-inactivated (60°C for 10 min)
anti-
i antibodies did not
diminish the effect of SRIF on K+
currents. We conclude that the
Gi-3 protein mediates the effect of SRIF on voltage-gated K+
currents in ovine somatotrophs.
pituitary; growth hormone; patch clamp; signaling; antibodies; dialysis
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INTRODUCTION |
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A NUMBER of different ion channels in the somatotroph cell membrane are modified by somatostatin (SRIF), leading to a reduction in growth hormone (GH) secretion (7). The direct mechanism for such a reduction in GH secretion is a decrease in intracellular free Ca2+ concentration ([Ca2+]i). Such an effect can be achieved by a decrease in transmembrane Ca2+ currents, as has been observed in pituitary somatotrophs (4, 8, 20) and neurons (15, 25). The reduction in Ca2+ influx can also be reached by an indirect mechanism through the action of SRIF on K+ channels. It has been shown, in rat somatotrophs, that SRIF increased several types of K+ currents including voltage-gated transient (IA) and delayed rectifying (IK) currents (6, 9) as well as inwardly rectifying K+ currents (24).
The SRIF receptor has a structure that typically couples to G proteins
(1). It has been suggested that G proteins mediate the effect of SRIF
on Ca2+ currents (4, 8, 15, 25).
The effect of SRIF on K+ currents
has also been demonstrated to be an action coupled by G protein (18,
19). Subtypes of the SRIF receptor are thought to be coupled to
different types of G protein (1), and the Gi protein is believed to mediate
the effect of SRIF on K+ channels
(32) in GH tumor cells. It has recently been demonstrated that
Go-2 protein mediates the effect
of SRIF on membrane Ca2+ currents
in "normal" ovine somatotrophs in primary culture (4); this
protein may also play a role in the effect of SRIF to reduce Ca2+ currents in
GH3 tumor cells (17). The subtype
of G protein mediating the augmentation of
K+ currents by SRIF is, however,
not clear. The present study aimed to resolve this issue by dialysis of
antibodies against the -subunit of G proteins into cells to
functionally block the action of certain subtypes of G proteins. In
cultured ovine somatotrophs, we found that the
i-3-subunit of
Gi protein
(Gi-3) mediates the increase in
the voltage-gated K+ currents by
SRIF. The preliminary data have previously been reported at the
Australian Physiological and Pharmacological Society Symposium (3).
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MATERIALS AND METHODS |
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Cell preparation. Sheep pituitaries were obtained from a local abattoir and then subjected to collagenase-pancreatin treatment to liberate cells as described previously (5). Cell yield was usually >107 cells/pituitary gland, with >90% viability (trypan blue exclusion test). The cell suspension (3-5 ml) was placed, under sterile conditions, above a layered column of Percoll solutions of increasing density and centrifuged as previously described (5). Cells in fractions 1 and 2 contained up to 85% of somatotrophs and were plated onto 35-mm petri dishes and used in these experiments (5). Electrophysiological recordings were made after 4-14 days in culture in a humidified incubator (37°C, air 95%-CO2 5%). In each case penicillin-streptomycin was used in the culture for the first 24 h in vitro. The culture medium was then changed every 48 h by using DMEM plus 10% sheep serum and 2% FCS.
Cell dialysis and experimental design.
Cell dialysis via patch pipette of molecules of various molecular
weights was carefully studied by Pusch and Neher (21). From their
equations and our previous experience (4), ~72% of the antibody
concentration in the patch pipette was dialyzed into the cell within 25 min with an electrode of resistance of 5 M. We therefore used a
dialysis time of 25 min to allow adequate transfer of the antibodies
into the cell.
Immunocytochemistry. As described in our previous experiments, an immunofluorescent staining technique was used to verify the dialysis of antibodies into the cell (4). After electrophysiological recordings with electrode solution containing antibodies, recorded cells were washed in PBS and fixed in 4% paraformaldehyde for 15-30 min. The cells were then incubated in 50:50 acetone-methanol for 3 min, washed with PBS, and then incubated for 30 min in PBS containing 5% horse serum to eliminate nonspecific binding. After further washing with PBS, the cells were exposed to a 1:30 (as suggested by the producer) dilution of FITC-conjugated anti-rabbit IgG antibodies for 1 h at room temperature and then mounted under coverslips in 70% glycerol for storage at 4°C before viewing. Negative control was established on the dishes without antibody dialysis and no cells stained positive. Only cells dialyzed with rabbit antibodies stained positive.
Electrophysiological recording.
Transmembrane currents were recorded by using the "gigaseal"
patch-clamp technique in WCR configuration (14), and the peak value of
each current trace was reported here. All recordings were made with the
Axopatch 200 amplifier, and electrodes were pulled by a Sutter P-87
microelectrode puller from borosilicate micropipettes coated with wax
and fire polished. The tip resistance of the electrode filled with
internal solution ranged from 2 to 5 M. Recordings were made on the
stage of an Olympus inverted microscope. The bath solution was composed
of the following: 140 mM NaCl, 0.5 mM
CaCl2, 1 mM
CdCl2, 5 mM KCl, 0.5 mM
MgCl2, 10 mM HEPES, 10 mM glucose,
and 1 µM tetrodotoxin at pH 7.4 and osmolarity of 310 mosM. The
electrode solution was composed of the following: 140 mM KCl, 10 mM
EGTA, 1 mM MgCl2, 10 mM HEPES, and
10 mM glucose. An ATP regenerative system (2 mM ATP, 5 mM
phosphocreatine disodium salt, and 20 U/ml creatine kinase) and the
antibodies were added into the electrode solution just before
recording, and the electrode solution was adjusted to pH 7.4 and
osmolarity of 300 mosM.
Data analysis and chemicals. Figures showing K+ current data represent one example from a group of experiments. The data are presented as means ± SE calculated from at least six experiments. Effects of treatments were considered significant at P < 0.05 level by ANOVA.
Culture media were obtained from Cytosystems (Castle Hill, NSW, Australia), sera and pancreatin were from GIBCO (Gaithersburg, MD), collagenase was obtained from Worthington Biochemical (Freehold, NJ), and SRIF was purchased from Auspep (Parkville, VIC, Australia). Antibodies to ![]() |
RESULTS |
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Evidence for successful dialysis of antibodies into recorded cells. The dialysis of antibodies into cells was verified by immunofluorescent staining with FITC-conjugated anti-rabbit IgG antibodies. The staining of the recorded cells indicates that the antibodies were successfully and specifically dialyzed into the cell during the WCR (Fig. 1). Similar results were obtained for all cells in this experiment with dialysis of antibodies.
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Effect of guanosine
5'-O-(3-thiotriphosphate) or
guanosine 5'-O-(2-thiodiphosphate) on
voltage-gated K+
current response to SRIF.
It has been shown that SRIF causes an increase in voltage-gated
K+ currents in rat somatotrophs
(9). In ovine somatotrophs, two types of voltage-gated
K+ currents were recorded as
transient, 4-aminopyridine-sensitive IA current and
delayed rectifying, tetraethylammonium-sensitive IK current, with
the IK being
dominant (5). The peak voltage-gated K+ current (combined
IA and
IK) was
subsequently investigated in this experiment to simplify the data.
Local administration of SRIF increased both
IA and
IK currents
without preference in this experiment in agreement with our previous
observation in rat somatotrophs (9). Such an increase in the
voltage-gated K+ currents induced
by 10 nM SRIF was reversible (Fig. 2,
A and C) after removal of SRIF. When
guanosine
5'-O-(3-thiotriphosphate) (GTPS, 200 µM) was included in the electrode solution, application of SRIF increased K+ currents, but
this increase was not reversible after removal of SRIF (Fig. 2,
B and
D). When guanosine
5'-O-(2-thiodiphosphate) (GDP
S, 200 µM) was included in the electrode solution, the first application of SRIF induced a reversible increase in the voltage-gated K+ currents that was the same as
the control group (Fig. 3,
A and C). After exposure to SRIF one or
two times in the presence of GDP
S in the electrode, the increase in
the K+ currents induced by SRIF
was totally abolished, whereas the cells in the control group responded
to SRIF in a manner compatible with that seen after the first
application of SRIF (Fig. 3, B and
C). This is probably due to an
increase in diffusion of GDP
S to the area close to G protein
and/or the competition of GDP
S with GTP in the cell for the
replacement of GDP binding of
-subunits during response to SRIF.
Dialysis of GDP
S did not affect the kinetics or amplitude of the
K+ currents. These effects of
GTP
S and GDP
S dialysis strongly confirmed the involvement of G
proteins in the voltage-gated K+
current response to SRIF.
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Dialysis of antibodies on
K+ current
response to SRIF.
Dialysis of antibodies did not affect the kinetics of the voltage-gated
K+ current (see below). With WCR
using anti-i-1-3
antibodies in the pipette, the increase in
K+ current by SRIF (10 nM) was
obtained within 5 min of establishing WCR (Fig.
4B, traces
at top). This response diminished
when SRIF was given a second time after 25 min of dialysis with
anti-
i-1-3 antibodies
(Fig. 4B, traces at
bottom). With
anti-
o-antibodies in the
electrode solution, the increase in
K+ current by SRIF (10 nM) after
25 min of dialysis was similar to the control responses (Fig.
4A). Dialysis with heat-inactivated (60°C for 10 min)
anti-
i-1-3-antibodies did
not affect the K+ current response
to SRIF after 25 min of dialysis (results not shown). Dialysis of
anti-
o- or
anti-
i-1-3-antibodies did not change the basal voltage-gated
K+ current recorded by
depolarizing the membrane potential from a holding potential of
80 to +20 mV (Fig. 4, A and
B). The change in
K+ current density
(K+ current/unit capacitance) from
a group of eight cells is shown in Fig.
4C, indicating that
anti-
i-1-3-antibodies
significantly (P < 0.01) decreased
the K+ current response to SRIF.
This dialysis of
anti-
i-1-3-antibodies blocked the response to SRIF even when a very high dose of SRIF (10
6 M) was used (6.5% of
initial response, n = 5; data not
shown). When
anti-
o-antibodies were
included in electrode solution, the modification of the SRIF
response did not occur (Fig.
4C).
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DISCUSSION |
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This experiment provides convincing evidence that the action of SRIF on
voltage-gated K+ currents in ovine
somatotrophs is mediated by Gi-3
protein. Structurally, the receptors for SRIF on somatotrophs are of
the type that contains seven transmembrane domains, suggesting that
they couple to G proteins (1). Several lines of evidence in support of
this notion use various approaches, such as direct application of
purified Gi protein in
inside-out patch-clamp recording (32), pretreatment of cells with
pertussis toxin, which abolishes the function of certain types of G
proteins (27), or intracellular application of GTP
S to abolish the
deactivation of G proteins after the activation by SRIF (13, 27). The
types of K+ channels that may be
modified by SRIF in various tissues include inwardly rectifying
K+ channels
(Kir), ATP-sensitive
K+ channels
(KATP),
Ca2+-activated
K+ channels, and voltage-gated
K+ channels (2, 9, 28, 30). In the
present experiment, we showed that the increase in voltage-gated
K+ currents by SRIF became
irreversible after intracellular dialysis with GTP
S and were
abolished after dialysis with GDP
S. These data strongly suggest that
the action of SRIF on voltage-gated K+ channels is mediated by G
proteins.
This finding was extended to the subtypes of G proteins by using
antibody dialysis techniques recently established in our laboratory
(4). Dialysis of antibodies against the
i-3-subunit significantly
attenuated the SRIF-induced augmentation of the voltage-gated
K+ currents, whereas antibodies
against the
i-1-2- or
o-subunits did not. This
therefore indicates that the G protein transducing the SRIF-induced
increase in voltage-gated K+
currents in ovine somatotrophs is
Gi-3 protein. In human GH tumor cells, it has recently been reported that the same type of G protein mediates the action of SRIF on Kir
currents using similar techniques (microinjection of antibodies) (28).
This suggests that a similar signaling system be used by SRIF to
increase both voltage-gated K+
currents and Kir currents. Because
of the ubiquitous distribution of multiple types of G proteins,
detailed study of the subtypes of G proteins at single cell level is
required to resolve which subunits mediate particular responses.
Intracellular dialysis of antibodies and/or antisense
oligonucleotides via patch-clamp electrode provides a powerful approach
in this regard (4).
In ovine somatotrophs, we previously demonstrated that modulation of
voltage-gated K+ currents altered
the membrane resting potential as well as the shape and timing of
action potentials (5). Increases in these K+ currents by SRIF will
contribute to the inhibition of GH secretion by SRIF via a reduction in
Ca2+ influx through voltage-gated
Ca2+ channels (5, 9). Existing
evidence also indicates that the reduction in voltage-gated
Ca2+ currents induced by SRIF is
partially responsible for the decrease in
Ca2+ influx (4, 8, 20, 29). Other
types of K+ currents, such as
Kir and
KATP, play pivotal roles in
maintenance of the resting membrane potential and are enhanced by SRIF
in pituitary or pancreatic -cells (2, 16, 28). We did not observe
significant Kir or
KATP currents in ovine
somatotrophs (5); this may reflect a species difference or a difference in experimental conditions.
Ca2+-activated
K+ channels have recently been
reported to regulate the release of prolactin in rat pituitary cells
(30) but may not be involved in the response to SRIF in somatotrophs.
It is likely that the inhibitory effect of SRIF on GH secretion is
achieved by its action on multiple types of SRIF receptors in pituitary
somatotrophs to modify multiple types of ion channels on the cell
membrane.
The second messenger systems responsible for the increase in
K+ currents is not yet clear. The
i-subunit of
Gi protein mediates the inhibitory
effect of SRIF on cAMP production in neurons (31). There is evidence,
however, to suggest an uncoupling between cAMP and the effect of SRIF
on K+ channels in human or rat
pituitary adenoma cells (10, 26). Phosphorylation of
K+ channel proteins has been
linked to a change of K+
conductance of Ca2+-activated
K+ channels (11), probably through
protein kinase (PK) C activation (23). It is still not clear whether
such a system is involved in the action of SRIF on voltage-gated
K+ channels. It has been shown in
GH4 cells that a cell-permeable cAMP analog reduced the voltage-gated
K+ currents and this was
completely reversed by SRIF (10). This indicates that SRIF may not act
on voltage-gated K+ channels via
the reduction in cAMP levels or subsequent reduction in PKA activity.
In addition, the action of SRIF on voltage-gated K+ channels was recorded in
classical whole cell patch-clamp configuration. Cytoplasm second
messenger systems may have been washed out during recording; therefore
they may not be the major component linking SRIF receptor and
voltage-gated K+ channels. It is
likely that the observed increase in voltage-gated K+ currents in ovine somatotrophs
is mediated by membrane-delimited signaling molecules, such as G
proteins.
Several types of SRIF receptor have been cloned and classified as SSTR1-5, with SSTR2 being divided into SSTR2A and SSTR2B (22). SSTR2, SSTR4, and SSTR5 have been located in pituitary cells and are coupled to Gi-1, Gi-3, and Go proteins (22). These G proteins are presumably involved in various effects of SRIF, including a reduction in cAMP levels (12), an increase in K+ currents (6, 9), and a decrease in Ca2+ currents (4, 8). By use of relatively selective agonists for SSTR2 and SSTR5 receptors, these subtypes were shown to mediate the action of SRIF on Ca2+ channels (29). It is not clear so far which subtype or subtypes of SRIF receptor mediate the increase in K+ currents by SRIF. However, it is now clear that, in ovine somatotrophs, SRIF acts on voltage-gated Ca2+ and K+ channels via two different G proteins, Go-2 and Gi-3.
We conclude that the effect of SRIF on voltage-gated K+ currents in somatotrophs is mediated by Gi-3 proteins. Go, Gi-1, and Gi-2 proteins are not involved in the coupling of the increase in voltage-gated K+ currents by SRIF.
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ACKNOWLEDGEMENTS |
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I thank Dr. I. J. Clarke and Dr. P. D. Marley for critical reading and discussion of the manuscript, K. Loneragan for technical assistance, and S. Panckridge for preparing the graphics.
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FOOTNOTES |
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This work was funded by grants from the Australian National Health and Medical Research Council.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: C. Chen, Prince Henry's Institute of Medical Research, PO Box 5152, Clayton, VIC 3168, Australia.
Received 25 February 1998; accepted in final form 21 April 1998.
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