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Merck Research Laboratories, Rahway, New Jersey
Submitted 24 October 2005; accepted in final form 7 February 2006
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ABSTRACT |
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S, an agent that blocks G protein activity. Taken together, these differential effects of galanin and GALP may provide a neurophysiological mechanism through which galanin and GALP differentially regulate energy balance, reproductive function, and other physiological processes. |
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INTRODUCTION |
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). Although sharing a common sequence (Ohtaki et al. 1999) and presumably activating the same group of receptors (Gundlach 2002), galanin and GALP exert distinct in vivo effect, in particular in the regulation of feeding behaviors. Chronic intracerebral ventricular (icv) administration of galanin in rats persistently upregulates food intake (Kyrkouli et al. 1990) but does not affect body weight (Smith et al. 1994), whereas icv administration of GALP in rats produces a dichotomous effect: a transient orexigenic effect followed by either significantly reduced or unchanged feeding behaviors (Lawrence et al. 2002; Seth et al. 2003). The molecular and cellular basis for the differential in vivo effects of galanin and GALP has not been elucidated.
The only known potential in vivo substrates for galanin and GALP are three subtypes of galanin receptors (Gal1-3), all three of which exhibit binding affinity for both galanin and GALP in physiological concentration ranges (Gundlach 2002; Lang et al. 2005). With the caveats that there may exist undiscovered selective receptors for either galanin or GALP, one possibility is that the distinct in vivo actions of galanin and GALP are mediated by their differential interactions with these three known receptors. This model predicts that galanin and GALP differentially regulate certain neuronal activities at the cellular level. We explored this possibility by comparing galanin and GALP effects on both synaptic transmission and intrinsic membrane properties of neurons in the arcuate nucleus (Arc), a brain region that extensively expresses all three galanin receptors and critically regulates feeding behaviors, reproductive function and other neuroendocrinological processes (Mennicken et al. 2002; Mitchell et al. 1997; O'Donnell et al. 1999). Here we have demonstrated in this study that galanin and GALP regulate synaptic transmissions in a very similar manner but differentially modulate the intrinsic membrane properties of the Arc neurons. Furthermore, we observed that the galanin effect on the membrane property was prevented by GALP. Our results provide a potential neurophysiological mechanism through which galanin and GALP differentially regulate various physiological and pathophysiological processes.
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METHODS |
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Hypothalamic brain slices were prepared as described previously (Glaum et al. 1996). Briefly, Sprague Dawley rats of either sex at age of 22–28 postnatal days were anesthetized with halothane. The rat was decapitated, and the brain was rapidly removed, blocked and placed in chilled (0–6°C) low-Ca2+ artificial cerebrospinal fluid (ASCF) containing (in mM) 126 NaCl, 1.6 KCl, 0.625 CaCl2, 0.6 MgSO4, 1.25 NaH2PO4, 18 NaHCO3, and 11 D-glucose (gassed with 95% O2-5% CO2, pH 7.4; osmolarity = 310 mosM). Coronal slices (260 µm) containing the arcuate nucleus of the hypothalamus were cut with vibratome (Leica, Germany). Slices were incubated at 30–32°C in regular ACSF [which contained (in mM) 126 NaCl, 1.6 KCl, 2.5 CaCl2, 1.3 MgSO4, 1.25 NaH2PO4, 18 NaHCO3, and 11 D-glucose, osmolarity = 300 mosM] bubbled with 95% O2-5% CO2.
Electrophysiology
The slice was transferred to a submersion chamber and continuously perfused with heated ACSF (33°C) at a rate of 2.5 ml/min. Cells were visualized with an upright microscope using infrared illumination. Cells located in the medial and ventral Arc were preferentially selected for recordings. To study synaptic transmission, whole cell voltage-clamp recordings were made with a multiclamp 700B amplifier (Molecular Device). A bipolar stimulating electrode was placed 100–300 µm rostral to the recording electrode to stimulate excitatory afferents at 0.1 Hz. For excitatory postsynaptic current (EPSC) recordings, electrodes (2–6 M
) contained (in mM) 130 Cs-methansulfate, 10 KCl, 10 HEPES, 0.4 EGTA, 2.0 MgCl2, 2.5 MgATP, and 0.25 Na3GTP (pH 7.2–7.4), 275–285 mosM. Fast inhibitory transmission was blocked by adding 100 µM picrotoxin in bath. Cells were held at –60 mV. For inhibitory postsynaptic current (IPSC) recordings, electrodes contained (in mM) 100 Cs-methansulfate, 40 KCl, 10 HEPES, 0.4 EGTA, 2.0 MgCl2, 2.5 MgATP, and 0.25 Na3GTP (pH 7.2–7.4), 275–285 mosM. Excitatory transmissions were blocked by adding 2 mM kynurenic acid in bath and miniature (m) IPSC recordings were obtained by adding additional 1 µM TTX in bath. Cells were held at –10 mV. Synaptic currents were recorded for 5–15 min to ensure stability, and then galanin or GALP was applied through perfusion system for 5 min.
To study the spontaneous action potential firing and oscillation of resting membrane potentials, whole cell current-clamp recordings were made with a Axopatch 200B amplifier (Molecular Device). Electrodes (2–6 M) contained (in mM) 130 K-methansulfate, 10 KCl, 10 HEPES, 0.4 EGTA, 2.0 MgCl2, 2.5 MgATP, and 0.25 Na3GTP (pH 7.2–7.4), 275–285 mosM. Spontaneous spike firings were recorded for 3–5 min for baseline, and then galanin or GALP was applied directly to the recording chamber. The final concentrations were calibrated as previously described (Fong and Van der Ploeg 2000). All quantitative measurements were taken 0.5–3 min after drug application. To measure the change in spontaneous firing, 60-s intervals of baseline and drug treatment were compared; to measure the change in the resting membrane potential, the baseline membrane potential, measured within 60 s prior to drug application, was compared with the greatest achievable hyperpolarization during 0.5- to 3-min interval after drug application. All drugs were purchased from Sigma except galanin and GALP from Biochem.
Data analysis
Cells that responded to drug application by 
15% changes were considered to have responded positively. Miniature IPSCs were analyzed using software minianalysis 6.0 and confirmed visually. Student's t-test was used for all data comparisons except for Figs. 5, C and D, and Fig. 6, C and D, in which a mixed-design two-way ANOVA and within-subject one-way ANOVA were applied, respectively. Post hoc pairwise comparisons of means were conducted using the Tukey HSD procedure with alpha = 0.05. Data are expressed as means ± SE.
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RESULTS |
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To begin to explore the possible differential cellular effects of galanin and GALP, we first focused on synaptic transmission using whole cell voltage-clamp recordings in brain slices containing the Arc. It has been shown that galanin presynaptically inhibits glutmatergic transmission (Kinney et al. 1998) in Arc neurons. We thus compared galanin and GALP effects on EPSCs by sequentially applying galanin and GALP to the recorded Arc neurons. Application of galanin (0.1 µM) and GALP (0.1 µM) induced similar reversible inhibition of EPSCs in Arc neurons (relative amplitude, galanin, 0.61 ± 0.05; GALP, 0.66 ± 0.04, n = 7, Fig. 1).
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). Having found no obvious differential effect of galanin and GALP on EPSCs we then examined their effect on the IPSCs in Arc neurons, an effect that has never been explored. When bath applied, both galanin and GALP significantly inhibited IPSCs in the Arc neurons (relative amplitude, galain, 0.47 ± 0.17, n = 6; GALP, 0.41 ± 0.13, n = 4, Fig. 2, A–C) in a similar way. When galanin and GALP were applied sequentially, cells that responded to galanin also responded to GALP perfusion with no exception (n = 5, Fig. 2D1). Furthermore, it appears that galanin and GALP can occlude each other's effect because in the presence of galanin, additional application of GALP did not produce further inhibition (n = 3, Fig. 2D2).
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Modulation of intrinsic membrane properties
Having established that in a very similar way galanin and GALP modulate synaptic transmissions in Arc neurons, we next focused on another important form of neuronal activity, the intrinsic membrane property. The Arc neurons have relatively depolarized resting membrane potentials (approximately –50 mV) and spontaneously fire action potentials. In theory, the spontaneous spike firing can serve as an indicator of general intrinsic excitability as it integrates functions of all ionic conductances. The rhythmic spiking activities in Arc neurons govern the release of critical metabolic neuropeptides and thus are intrinsically implicated in regulation of appetite and feeding behaviors (Jobst et al. 2004). The spontaneous spike firing of Arc neurons is well preserved in acutely prepared brain slices and can be monitored with whole cell current-clamp recordings. Our results indicate that galanin and GALP differentially modulate the resting membrane potential and the spontaneous spike firing in Arc neurons.
In hypothalamic slices, the Arc neurons spontaneously and steadily fire action potentials with a frequency of 1–6 Hz from the resting membrane potential (–50.1 ± 1.7 mV, n = 37). Consistent with a previous observation (Poulain et al. 2003), after bath application of galanin (0.1 µM), the resting membrane potential was substantially and reversibly hyperpolarized (
V = 15.7 ± 1.8 mV, P < 0.01, n = 23, Fig. 4, A and E). At least partially due to this strong hyperpolarization, the spontaneous spike firing was either abolished or substantially reduced in most (42/44) of the recorded neurons (Fig. 4. A and D1). Furthermore, the reversal potential (–62 ± 3 mV, n = 3, data not shown) of the galanin-induced conductance is consistent with the reversal potential of K+ ([K+]i = 10 mM and [K+]o = 120 mM), suggesting the K+ channel (e.g., GIRK) as a downstream effecter for the galanin effect on membrane properties. In contrast, GALP (0.5 µM) did not alter the resting membrane potential of Arc neurons (V = 2.3 ± 1.2 mV, P > 0.1, n = 10, Fig. 4, B and E) but modulated the spontaneous spike firing. In response to GALP perfusion, about 1/3 of the recorded neurons (9/34) exhibited an increase in spontaneous spike firing, whereas about half of the cells (18/34) exhibited a decrease (Fig. 4, B and C). This differential effect is unlikely due to the insufficient stimulation or overstimulation of the presumable galanin/GALP receptors as it happened across a broad concentration range of galanin and GALP (Fig. 4D).
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The galanin/GALP receptors, which are extensively expressed in Arc (Horvath et al. 1995; Mitchell et al. 1997; O'Donnell et al. 1999; Mennicken et al. 2002), can modulate the ion channels on Arc neurons, thus directly affecting the intrinsic membrane properties and resulting in alterations in spontaneous spike firing. Alternatively, galanin and GALP can modulate the excitable state of Arc neurons by affecting presynaptic inputs, which as we previously demonstrated is likely mediated by the presynaptically located galanin/GALP receptors. At which location do galanin/GALP receptors mediate the differential effect on the intrinsic membrane properties? In an attempt to address this question, we examined the impact of selective blockade of postsynaptic galanin receptors. Without affecting the presynaptic receptors, selectively loading the cell with GDPS (500 µM), an agent that strongly blocks all G-protein-coupled receptors including the three types of galanin receptors, totally abolished galanin-induced hyperpolarization of the resting membrane potential (control, –44.4 ± 2.3 mV; galanin, –46.2 ± 3.0, P > 0.1, n = 12. Figure 6, A and D) as well as the reduction in spontaneous spike firing (relative firing rate with galanin, 0.91 ± 0.15, P > 0.1, n = 12; Fig. 6, A and C). In contrast, in the control experiment, selective blockade of Ca2+-dependent intracellular activity in Arc neurons with EGTA (20 mM) failed to block galanin's effect on either resting membrane potential or spontaneous spike firing (relative firing rate, 0.06 ± 0.06, P < 0.01, n = 6. resting membrane potential in mV, EGTA alone, –52.0 ± 2.7; EGTA + galanin, –59.6 ± 2.5, P < 0.05, n = 6. Fig. 6, B and D). Taken together, our data suggest that galanin/GALP receptors located on the recorded Arc neurons are essential in mediating the differential effect.
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DISCUSSION |
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) and differentially regulate feeding behavior, hormone secretion, reproductive cycle, pain, and learning and memory (Gundlach 2002). Our study indicates that galanin and GALP suppress both inhibitory and excitatory synaptic transmissions in a similar manner, while differ in their modulation of membrane and firing properties of the Arc neurons. These cellular functions of galanin and GALP may help us understand the complex in vivo effect of galanin and GALP.
Whereas GALP uniformly suppresses synaptic transmissions (both IPSCs and EPSCs) in the Arc neurons, its effect on firing properties diverges to two directions: it increases the action potential firing in half of the Arc neurons while decreases the firing in the other half. This dichotomous effect may reflect two distinct populations of neurons that possess different receptors and/or intracellular signalings responding to GALP. The candidate populations of Arc neurons are the CART/POMC neurons, which express anorexigenic peptide cocaine and amphetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone (
-MSH) derived from the Proopiomelanocortin (POMC) precursor, and the NPY/AgRP neurons, which express orexigenic peptide neuropeptide Y (NPY) and agouti-related peptide (AgRP) (Chen et al. 1999; Schwartz et al. 2000). These two types of neurons comprise the majority of Arc neurons and exhibit population-specific responses to orexigenic and anorexigenic neuropeptides. For example, the CART/POMC neurons become more excitable, whereas the NPY/AgRp neurons become less when anorexigenic peptide leptin (Cowley et al. 2001) or PYY3–36 (Batterham et al. 2002) is applied. Conversely, the CART/POMC neurons become less excitable, whereas the NPY/AgRP neurons become more when orexigenic peptide ghrelin (Cowley et al. 2003; van den Top et al. 2004) or orexin (Muroya et al. 2004) is applied. Given that the activation state of NPY/AgRP and CART/POMC neurons critically determines the feeding behavior (Gropp et al. 2005; Luquet et al. 2005), such population-selective effect may serve as a cellular mechanism for these orexigenic and anorexigenic peptides to modulate food intake and body weight. A critical future study would be to examine whether the two populations of Arc neurons, categorized by their differential response to GALP, coincide with CART/POMC neurons and NPY/AgRP neurons, which will provide a potential cellular basis for the in vivo anorexigenic effect of GALP.
Another important question is why galanin and GALP sometimes share similar feature, whereas some other times differ in their cellular effects. We propose that their unique interactions with galanin receptors underlie these effects. Radioligand-binding and [35S]GTP
S-binding studies have demonstrated that both galanin and GALP interact with GAL1 and GAL2 receptors in vitro (Ohtaki et al. 1999) but with different affinity and activation potency. Galanin exhibits a similar binding affinity (5-fold higher for GAL1) and similar in vitro functional potency for all GAL1-3 receptor, whereas GALP exhibits an 
20-fold higher affinity for GAL2 and GAL3 receptors than GAL1 receptors and 180-fold higher in vitro functional potency for GAL2 receptors than GAL1 receptors (Lang et al. 2005; Ohtaki et al. 1999). Galanin and GALP bind and activate GAL2 receptors with an approximate equal affinity and potency. Galanin is able to bind to and activate GAL3 receptor, resulting in activation of G-protein-coupled inwardly rectifying K+ channels (Smith et al. 1998). GALP binds to GAL3 receptors with higher affinity than binding to GAL1 and GAL2 receptors (Lang et al. 2005), but the physiological consequence of GALP binding to GAL3 receptor is unclear.
The similarity between galanin and GALP in modulating synaptic transmission suggests that the mediating receptors possess similar binding affinity and functional potency to both galanin and GALP, a feature consistent with the in vitro properties of GAL1 and GAL2 receptors. Our results show that both galanin and GALP increase paired pulse ratio and decrease the frequency of mIPSCs without affecting the amplitude, strongly suggesting presynaptic action of the receptors. Taken together, the preceding data support an idea that the presynaptic GAL1/2 receptors mediate the effect of galanin and GALP on synaptic transmission. It is worth noting that the preceding data do not exclude a role for the postsynaptically located GAL1/2 receptors, which may function to release retrograde messengers thus inhibiting presynaptic release.
Which receptor(s) mediate the differential effect of galanin and GALP on the intrinsic membrane property? A study combining sharp-electrode recording with mRNA labeling correlates galanin-induced hyperpolarization of the resting membrane potential with a positive GAL1 receptor signal in Arc neurons, suggesting that GAL1 receptors mediate galanin's effect on intrinsic membrane properties (Poulain et al. 2003). However, GAL1 receptors alone are not sufficient to mediate the antagonizing effect of GALP, which indeed has been demonstrated to be a GAL1 receptor agonist. An alternative candidate is the GAL3 receptor. GAL3 receptors are also highly expressed in the Arc and are activated by galanin to trigger a strong K+-mediated hyperpolarization in vitro (Smith et al. 1998), thus sufficiently mediating galanin-induced hyperpolarization of the resting membrane potential and suppression of spontaneous spike firing. GALP not only binds to GAL3 receptors but also competes and inhibits galanin's binding to GAL3 receptors. In addition, binding to GAL3 receptor by GALP does not trigger detectable activations of intracellular signaling (Lang et al. 2005). It is tempting to speculate that GALP may act as an endogenous antagonist or partial agonist on GAL3 receptors, therefore preventing or undermining galanin's action at GAL3 receptor. It remains, however, to be proven that GALP is the physiological antagonist/partial agonist of GAL3 receptor and that the galanin-induced hyperpolarization is stringently correlated with GAL3 receptor expression. Our results also do not exclude the possibility that there may be unidentified selective GALP receptors that mediate this differential effects.
Although our study emphasizes the galanin receptors, it is critical to bear in mind that other neuropeptide systems may significantly contribute to the differential in vivo effects of galanin and GALP by controlling their production and release. For example, leptin modulates both galanin- and GALP-producing cells and increases GALP productions (Sahu 2003). It is also important to consider other brain regions that receive galanin and GALP projections when interpreting in vivo observations. For example, the paraventricular nucleus (PVN) receives both galanin and GALP projections and expresses all three types of galanin receptors (Gundlach and Burazin 1998; Larm and Gundlach 2000; Lu et al. 2005), and intra-PVN administrations of galanin and GALP result in robust differential feeding responses (Seth et al. 2003). Nonetheless, further studies are required to fully understand the cellular basis of the in vivo differentiation between galanin and GALP. As the beginning of this line of study, our results begin to delineate a neurophysiological link, which may facilitate future studies of galanin and GALP signaling.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Y. Dong, Merck Research Laboratories, P. O. Box 2000; R80M213, Rahway, NJ 07065 (E-mail: yan_dong{at}merck.com)
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ABSTRACT
INTRODUCTION
