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NERVOUS SYSTEM CELL BIOLOGY

Leptin and CCK modulate complementary background conductances to depolarize cultured nodose neurons

Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, College of Veterinary Medicine, Washington State University, Pullman, Washington

Submitted 30 August 2005 ; accepted in final form 26 September 2005

	ABSTRACT

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We have previously reported that intraceliac infusion of leptin induces a reduction of meal size that depends on intact vagal afferents. This effect of leptin is enhanced in the presence of cholecystokinin (CCK). The mechanisms by which leptin and CCK activate vagal afferent neurons are not known. In the present study, we have begun to address this question by using patch-clamp electrophysiological techniques to examine the mechanisms by which leptin and CCK activate cultured vagal afferents from adult rat nodose ganglia. We found that leptin depolarized 41 (60%) of 68 neurons. The magnitude of membrane depolarization was dependent on leptin concentration and occurred in both capsaicin-sensitive and capsaicin-insensitive neurons. We also found that a majority (16 of 22; 73%) of nodose neurons activated by leptin were also sensitive to CCK. CCK-induced depolarization was primarily associated with the increase of an inward current (11 of 12), whereas leptin induced multiple changes in background conductances through a decrease in an outward current (7 of 13), an increase in an inward current (3 of 13), or both (3 of 13). However, further isolation of background currents by recording in solutions that contained only sodium or only potassium revealed that both leptin and CCK were capable of increasing a sodium-dependent conductance or inhibiting a potassium-dependent conductance. Our results support the hypothesis that vagal afferents are a point of convergence and integration of leptin and CCK signaling for control of food intake and suggest multiple ionic mechanisms by which leptin and CCK activate vagal afferent neurons.

cholecystokinin; vagal afferents; capsaicin; satiation

Vagal afferent neurons innervate a majority of the abdominal viscera and express both leptin and CCK receptors (4–6, 17). It is well established that satiation produced by peripheral CCK involves activation of vagal afferent neurons (10, 21, 29, 30, 32). On the other hand, many effects of leptin on food intake are associated mainly with actions on neuronal populations within the hypothalamus (27, 33, 36, 38). However, in 1998, Bado et al. (1) demonstrated that leptin is prandially released from the stomach and may act locally to influence gastrointestinal physiology. Furthermore, a growing number of reports have suggested that subdiaphragmatic vagal afferent neurons, which innervate the stomach and intestinal tract, may also be a site for leptin action. Intraceliac arterial application of leptin results in a decreased intake of a sucrose meal via a mechanism dependent on capsaicin-sensitive vagal afferent neurons (19). This satiation effect of leptin is synergistically enhanced by the presence of CCK (19). Extracellular single-unit recordings indicate that exogenous leptin alters the firing rate of vagal afferent fibers and that at least some of leptin-activated fibers are also activated by CCK (35). Finally, using cultured nodose ganglion neurons, we demonstrated that leptin rapidly increases cytosolic calcium in vagal afferents (18). The leptin-induced calcium signals also were synergistically enhanced by the presence of CCK (18). Taken together, these observations suggest that vagal afferent neurons are a target for acute leptin-CCK interaction.

Although multiple investigations using extracellular recording have observed effects of leptin on vagal afferent fiber activity, there have been no investigations of the mechanisms by which leptin activates vagal afferents in vitro. Furthermore, while a direct depolarizing effect of CCK on cultured nodose neurons has been reported by us and others (9, 29), the ionic mechanism associated with CCK-induced activation of these neurons is not known. Therefore, in the current study, we used perforated patch electrophysiological techniques to investigate the membrane changes by which leptin and CCK activate vagal afferent neurons in culture. We found that leptin reversibly depolarized a subpopulation of cultured nodose neurons, a majority of which were capsaicin sensitive. Many of these neurons were also activated by CCK. The depolarization induced by both leptin and CCK was a result of modest changes in resting background conductances, which tended to be distinct and complementary under physiological conditions. These results suggest potential mechanisms through which leptin and CCK may cooperate to depolarize vagal afferents and thereby contribute to vagal afferent control of food intake and visceral functions.

	METHODS

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Cell culture. Dissociated vagal afferent cell bodies were obtained as previously described (29). Nodose ganglia, which contain the vagal afferent cell bodies, were isolated from anesthetized (25 mg/100 g ketamine, 2.5 mg/100 g xylazine) adult male Sprague-Dawley rats (280–320 g) under aseptic conditions. All animal procedures performed were approved by the Washington State University Institutional Animal Care and Use Committee. The right and left nodose ganglia were pooled and digested for 90 min at 37°C in 3 ml of Ca²⁺- and Mg²⁺-free Hanks' balanced salt solution containing 1 mg/ml dispase II (Boehringer Mannheim, Indianapolis, IN) and 1 mg/ml collagenase type Ia (Sigma, St. Louis, MO). Cells were dispersed by gentle trituration through silanized Pasteur pipettes, washed two times with HEPES-buffered Dulbecco's modified Eagle's medium (HDMEM) (Life Technologies, Grand Island, NY) containing 10% fetal calf serum (Life Technologies) supplemented with antibiotic (penicillin-streptomycin, 100 U/ml and 100 µg/ml, respectively), and then plated onto poly-L-lysine-coated coverslips and maintained in HDMEM with 10% fetal calf serum at 37°C in a 5% CO₂ atmosphere. All experiments were performed within 48 h after the nodose ganglia were collected.

Patch-clamp electrophysiology. All manipulations and measurements were made at room temperature (22°C) in a physiological saline composed of (in mM) 140 NaCl, 5 KCl, 2 CaCl₂, 1 MgCl₂, 6 glucose, and 10 HEPES, pH adjusted to 7.4 with Tris. The coverslips containing cultured nodose ganglion neurons were mounted into an open chamber and continuously perfused with physiological saline. Measurements were taken using a perforated patch technique with tapered borosilicate glass pipettes (World Precision Instruments, Sarasota, FL) backfilled with a saline solution approximating intracellular ionic concentrations (in mM: 10 NaCl, 12 KCl, 59 K₂SO₄, 4 MgCl₂, with 10 HEPES, pH adjusted to 7.4 with Tris, and 0.5 mg/ml nystatin). Data were collected using pCLAMP 9 software with an Axopatch 200A amplifier and a Digidata 1322A analog-to-digital converter (all from Axon Instruments, Union City, CA).

Experimental protocols. In all experiments, murine leptin (Pepro Tech, Rocky Hill, NJ) and the sulfated form of CCK-8 (Peptides International, Louisville, KY) were used. Leptin and CCK were initially disolved in pyrogen-free/sterile saline, aliquotted, and stored at –20°C until used for experimentation. Leptin and CCK were then diluted directly into the physiological saline bath solution. Solutions containing hormones were applied by switching solutions flowing through a common manifold upstream of the recording chamber (15 to 30 s required for new solution to reach neurons). Concentrations of hormones used are indicated in RESULTS.

Membrane potentials were recorded in current-clamp mode, and the voltage recordings were digitized at 2 kHz. Hormone-induced effects are reported as the change from baseline resting membrane potential. Current traces were recorded at a holding potential of –60 mV using the voltage-clamp configuration, and the current traces were digitized at 10 kHz. Data are expressed as the change in current from holding current. To test whether hormone-induced changes in holding current were due to increases or decreases in conductances, we applied a series of four voltage ramps (–80 to –40 mV in 2.5 s) before and after hormone application. The resulting current traces were averaged, and any measurements were made from the averaged trace. Summarized changes in voltage, current, or slope conductance are reported as means ± SE from neurons responsive to the particular hormone.

In the sodium-only experiments, sodium replaced all potassium in the bath and the pipette. In the potassium-only experiments, potassium replaced all sodium in the bath and pipette. These manipulations allowed us to detect changes in currents not carried by potassium and sodium, respectively. In these experiments, the cells were held at –60 mV throughout the recording (except when ramps were applied), and thus the potential depolarization caused by these manipulations and potential for cell rundown due to large calcium influxes were avoided.

	RESULTS

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Leptin evoked a reversible depolarization in 41 (60%) of 68 cultured nodose ganglion neurons tested. A subgroup of leptin-responsive neurons exposed to multiple leptin concentrations exhibited increasing depolarizing responses with increasing concentrations of leptin (1, 3, 10, and 30 ng/ml) (n = 13 neurons) (Fig. 1). Overall, action potential firing occurred in 8 (20%) of 41 leptin-responsive neurons when the highest concentration of leptin was applied (example not shown). In 18 leptin-responsive neurons tested with capsaicin, we found 13 (72%) to be capsaicin sensitive and 5 (28%) to be insensitive to capsaicin (Fig. 2).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Representative examples of membrane potential in cultured nodose neurons after bath application of leptin. The bars over the traces indicate the period of ligand application. Neurons were exposed to 1 ng/ml (A), 3 ng/ml (B), 10 ng/ml (C), and 30 ng/ml (D) leptin. The magnitude of the leptin response was dose dependent (E). *P = 0.009 compared with 1 ng/ml; **P = 0.033 compared with 1 ng/ml (2-tailed t-test).

View larger version (19K): [in this window] [in a new window]   Fig. 2. Leptin (Lept)-induced depolarization of cultured nodose neurons occurred in both capsaicin (Cap)-insensitive (A) and capsaicin-sensitive (B) neurons. The bars over the traces indicate when either leptin (40 ng/ml) or capsaicin (10 nM) was applied. Most the neurons responsive to leptin were also sensitive to capsaicin (see text).

View larger version (19K): [in this window] [in a new window]   Fig. 3. Overlap of responses to leptin (40 ng/ml) and cholecystokinin (CCK; 10 nM) in cultured nodose neurons. Bars above the traces indicate the period of ligand application. Cells were divided into four categories: responsive to leptin only (A), responsive to CCK only (B), responsive to both leptin and CCK (C), and nonresponsive (not shown).

View larger version (25K): [in this window] [in a new window]   Fig. 4. Change in background current in response to leptin (40 ng/ml) (A) and CCK (10 nM) (B) exposure in physiological solutions (neurons voltage clamped at –60 mV). Bars above the traces indicate the period of ligand application. Dotted lines indicate zero current. Periods denoted by a and b indicate when 4 voltage ramps (–80 to –40 mV in 2.5 s) were applied.

View larger version (25K): [in this window] [in a new window]   Fig. 5. Examples of membrane current responses to a depolarizing ramp protocol before (a) and after (b) ligand application in physiological solutions (ramp protocol described in Fig. 4). A: exposure to CCK (10 nM) decreased membrane slope conductance in 11 of 12 neurons tested. Leptin application resulted in three changes of membrane slope conductance: in recordings from 13 neurons, 7 exhibited a decrease in slope conductance (B), 3 produced an increase in slope conductance (C), and 3 showed no change in slope conductance (D).

View larger version (23K): [in this window] [in a new window]   Fig. 6. Membrane current responses to a depolarizing ramp protocol before (a) and after (b) ligand application under sodium-only (A and C) or potassium-only (B and D) conditions. Voltage ramps were applied as described in Fig. 4. In sodium-only conditions (see METHODS) exposure to leptin (A; 40 ng/ml) and CCK (C; 10 nM) increased inward current and the slope conductance in all neurons responsive to hormones (number tested indicated in panels). Under potassium-only conditions, exposure to leptin (B; 40 ng/ml) and CCK (D; 10 nM) decreased inward current and slope conductance in all neurons responsive to hormones (number tested indicated in panels).

	DISCUSSION

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Previous investigations using extracellular recording in vivo revealed that both leptin (35) and CCK (22) acutely activate vagal afferent neurons and that isolated nodose neurons also respond to direct application of leptin (18) and CCK (9, 18, 29). Results derived using cultured vagal afferents are significant in that they confirm that leptin and CCK activate vagal afferents directly rather than through the release of other bioactive substances from end organs or nerves. Nevertheless, the mechanisms by which leptin and CCK activate vagal afferent neurons have not been determined.

Using voltage ramp protocols in which the electrolyte composition in the bath and electrodes mimicked physiological conditions, we found that the major action of CCK is to activate an inward depolarizing conductance. In contrast, leptin-induced depolarizations were associated with multiple changes in membrane conductances. In about one-half of the neurons tested, leptin decreased an outward hyperpolarizing conductance. However, in some neurons, leptin increased an inward conductance, and in other neurons, both these actions occurred such that a net inward current was produced but the slope conductance of the neuron had minimal change.

Ion substitution experiments confirmed this multiple action of leptin. In sodium-only conditions, leptin induced an inward current that was associated with an increase in the slope conductance. This action is consistent with activating a sodium-dependent conductance, although in physiological conditions, such a conductance could be a mixed cationic conductance. In potassium-only conditions, leptin induced an increase in outward current associated with a decrease in the slope conductance, an action consistent with inhibiting a potassium-selective conductance. (In potassium-only conditions, the potassium-selective current is inward because of approximately equal potassium on both sides of the membrane and the use of a holding potential of –60 mV.) Such a conductance would be hyperpolarizing under physiological conditions. Thus leptin appears to activate nodose neurons by a dual action, increasing a depolarizing conductance while inhibiting a hyperpolarizing conductance. It is unknown whether one or another of these actions predominates in specific vagal afferent nerves (for example, A-type or C-type neurons or neurons that innervate different structures).

Previously, leptin has been shown to have both depolarizing (8, 20, 34) and hyperpolarizing (33, 34) effects, depending on which central neuronal populations were recorded. In general, leptin-induced depolarizations were a result of an increase in a nonspecific cation conductance (8, 20), whereas hyperpolarizations were due to increased potassium conductance through an ATP-sensitive channel (33). In contrast to central effects, we found that leptin acted exclusively to depolarize cultured nodose ganglion neurons. These leptin-induced depolarizations were primarily a result of a reduction of outward potassium conductance, but depolarization in some neurons also resulted from activation of an inward cation conductance. Determination of the exact channels targeted by leptin requires further study.

CCK has been shown to depolarize several different central and peripheral neurons, and these depolarizations have been associated with increases (13, 16, 24, 25, 26, 29), decreases (3, 13, 25, 38), or no change (13, 25) in input resistance. Such variable effects on input resistance have been found to occur even within the same preparation (13, 25). Our previous study (29) of current-clamp recordings of CCK actions on cultured nodose neurons was inconclusive regarding a consistent action of CCK on input resistance. Although we occasionally could resolve a decrease in input resistance associated with CCK-induced depolarization, more often no change in input resistance was detectable despite a robust depolarization. Our current findings support the conclusion that the primary action of CCK on nodose neurons is to activate a depolarizing conductance, although there was one exception (of 12 recordings), and in many cases, the change in slope conductance produced by CCK was rather small. Because the dominant effect of CCK in physiological solutions was to induce an inward current with an increase in slope conductance (signifying activation of a sodium or mixed cationic conductance), our expectation in ion substitution experiments was that CCK would preferentially have effects in the sodium-only condition, but that not much of an effect would occur in potassium-only conditions. While our expectation was met in the sodium-only measurements, surprisingly, we observed an inhibition of potassium current in the potassium-only condition that was of approximately the same magnitude as the effect of leptin on this current. The reason for the similarity in the magnitude of the effect is not readily apparent. However, it indicates that, like leptin, CCK appears also to have the ability to modify complementary conductances that lead to activation of nodose neurons. As with leptin, whether one action of CCK predominates within specific subgroups of vagal afferents requires further study.

Behaviorally, leptin (19) and CCK (23) enhance the process of satiation via a capsaicin-sensitive vagal mechanism. The ability of leptin and CCK to depolarize nodose neurons through predominately separate, although complementary, changes in background ionic conductances suggests a putative mechanism through which they may synergistically activate vagal afferent neurons. Whether acute interactions between leptin and CCK occur exclusively at the level of conductances present in the membrane of nodose neurons or involves activation of overlapping intracellular signaling cascades that in turn modify these conductances remains to be determined.

In summary, we report that leptin directly and acutely induces membrane depolarization in a subpopulation of cultured nodose neurons. Most of these leptin-sensitive nodose neurons were sensitive to capsaicin, and they were also depolarized by CCK. Under bath and pipette solutions that approximate physiological conditions, the predominant (but not exclusive) conductance targeted by leptin was inhibition of an outward current, whereas CCK preferentially activated an inward current. However, in ion-selective conditions, we were able to demonstrate that both leptin and CCK can activate a current carried by sodium and inhibit a current carried by potassium. It is unknown whether the molecular identities of these conductances and whether the exact same conductances are modified by both leptin and CCK. The actions of these hormones on these conductances are likely to underlie the synergistic effects of leptin and CCK to activate vagal afferent neurons at submaximal concentrations and may mediate endogenous interactions between leptin and CCK in the control of food intake and energy expenditure.

	GRANTS

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This work was funded in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-067146 (to S. M. Simasko).

	ACKNOWLEDGMENTS

 
We acknowledge the efforts of Dallas Kinch for the maintenance of the primary cultures of vagal afferent neurons.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. H. Peters, Program in Neuroscience, Dept. of VCAPP, College of Veterinary Medicine, Washington State Univ., Pullman, WA 99164-6520 (e-mail: petersj{at}vetmed.wsu.edu)

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.

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This Article Abstract Full Text (PDF) All Versions of this Article: 290/2/C427    most recent 00439.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Peters, J. H. Articles by Simasko, S. M. Search for Related Content PubMed PubMed Citation Articles by Peters, J. H. Articles by Simasko, S. M.