The Journal of Neurophysiology Vol. 78 No. 6 December 1997, pp. 3484-3488
Copyright ©1997 by the American Physiological Society

Inhibition of Dendritic Calcium Influx by Activation of G-Protein-Coupled Receptors in the Hippocampus

Huanmian Chen and Nevin A. Lambert

Department of Pharmacology and Toxicology, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Georgia 30912-2300

	ABSTRACT

Abstract Introduction Methods Results Discussion References

Chen, Huanmian and Nevin A. Lambert. Inhibition of dendritic calcium influx by activation of G-protein-coupled receptors in the hippocampus. J. Neurophysiol. 78: 3484-3488, 1997. G_i proteins inhibit voltage-gated calcium channels and activate inwardly rectifying K⁺ channels in hippocampal pyramidal neurons. The effect of activation of G-protein-coupled receptors on action potential-evoked calcium influx was examined in pyramidal neuron dendrites with optical and extracellular voltage recording. We tested the hypotheses that 1) activation of these receptors would inhibit calcium channels in dendrites; 2) hyperpolarization resulting from K⁺ channel activation would deinactivate low-threshold, T-type calcium channels on dendrites, increasing calcium influx mediated by these channels; and 3) activation of these receptors would inhibit propagation of action potentials into dendrites, and thus indirectly decrease calcium influx. Activation of adenosine receptors, which couple to G_i proteins, inhibited calcium influx in cell bodies and proximal dendrites without inhibiting action-potential propagation into the proximal dendrites. Inhibition of dendritic calcium influx was not changed in the presence of 50 µM nickel, which preferentially blocks T-type channels, suggesting influx through these channels is not increased by activation of G-proteins. Adenosine inhibited propagation of action potentials into the distal branches of pyramidal neuron dendrites, leading to a three- to fourfold greater inhibition of calcium influx in the distal dendrites than in the soma or proximal dendrites. These results suggest that voltage-gated calcium channels are inhibited in pyramidal neuron dendrites, as they are in cell bodies and terminals and thatG-protein-mediated inhibition of action-potential propagation can contribute substantially to inhibition of dendritic calcium influx.

	INTRODUCTION

Abstract Introduction Methods Results Discussion References

Activation of receptors that couple to G_i proteins (including G_i1-3 and G_o) inhibits high-threshold voltage-gated calcium channels in central neurons (Hille 1994). This phenomenon has been extensively studied in neuronal cell bodies and, more recently, in central nerve terminals, where the resulting decrease in calcium influx contributes to presynaptic inhibition of neurotransmitter release (Stanley and Mirotznik 1997; Wu and Saggau 1994a). In contrast, much less is known about G-protein-mediated inhibition of voltage-gated calcium channels in dendrites, in part because these processes cannot be adequately voltage-clamped in intact neurons.

There are a number of reasons to suspect that G-protein-mediated inhibition of calcium influx in hippocampal dendrites may differ from that in cell bodies or axon terminals. First, pyramidal cell bodies and dendrites possess different complements of voltage-gated calcium channels. High-threshold N-, L- and P/Q-type channels are predominantly located on cell bodies, whereas R-type and low-thresholdT-type channels are relatively abundant on dendrites (Christie et al. 1995; Magee and Johnston 1995). Pertussis toxin-sensitive G-proteins (G_i/G_o) usually inhibit high-threshold channels of the N- and P/Q-types, whereas L- and R-types are less sensitive or insensitive (Hille 1994), and low-threshold, T-type channels are usually not inhibited (Guyon and Leresche 1995). Thus the calcium channels present on pyramidal neuron dendrites may be less susceptible to direct inhibition by G-proteins than those on cell bodies or terminals. In addition, recent evidence suggests that direct inhibition of calcium channels by G-proteins requires intact syntaxin, a protein that is targeted to axon terminals (Stanley and Mirotznik 1997). Second, G_i proteins also activate inwardly rectifying K⁺ channels in pyramidal cells (reviewed in Jan and Jan 1997; Hille 1994), hyperpolarizing dendrites. In intact dendrites this could deinactivate T-type channels and increase calcium influx mediated by these channels. On the other hand, hyperpolarization could inhibit active propagation of action potentials into dendrites (Richardson et al. 1987; Turner et al. 1989) and indirectly decrease calcium influx.

The coincident activation of K⁺ channels and inhibition of some (but not all) Ca²⁺ channels makes the net effect of G-protein-coupled receptor activation on action-potential-evoked calcium influx in dendrites difficult to predict. We have performed a series of experiments to measure inhibition of dendritic calcium influx by activation of G-protein-coupled receptors and to determine if activation of inwardly rectifying K⁺ channels counteracts or adds to such inhibition. Our results suggest that G-proteins directly inhibit calcium channels in pyramidal neuron dendrites, as they do in cell bodies and terminals. Deinactivation of T-type calcium channels does not appear to counteract inhibition of high-threshold channels in pyramidal neuron dendrites. Activation of G-protein-coupled receptors that activate K⁺ channels inhibits action-potential propagation into distal dendritic branches, indirectly increasing inhibition of calcium influx in these branches as compared with cell bodies or proximal dendrites.

	METHODS

Abstract Introduction Methods Results Discussion References

Hippocampal slices (400 µm thick) were prepared from 21-60 day old Sprague-Dawley rats and maintained at 22°C in artificial cerebrospinal fluid (ACSF) that contained (in mM) 125 NaCl, 25 NaHCO₃, 3.3 KCl, 2 MgCl₂, 2 CaCl₂, and 20 D-glucose and was oxygenated with 95% O₂-5% CO₂. In all experiments the ACSF also contained 6,7-dinitroquinoxaline-2,3-dione (DNQX, 20 µM) and D,L-2-amino-5-phosphonovalerate (APV, 20 µM) to block ionotropic glutamate receptors, as well as picrotoxin (50 µM) to block -aminobutyric acid-A (GABA_A) receptors. Pyramidal cells were loaded with fura-2-AM essentially as described previously (Regehr and Tank 1991; Wu and Saggau 1994b); a suspension of fura-2-AM [dissolved in dimethyl sulfoxide (DMSO) and pluronic acid] in ACSF was pressure applied through a large patch pipette into stratum oriens of area CA1 for 15 min. After 1 h flourescence was monitored with an upright microscope (Olympus BX50WI) fitted with a ×40 water immersion objective, a 200 W Hg/Xe lamp (Optiquip), a fura-2 filter set (XF04, Omega Optical), an electromechanical shutter (Vincent), and a photomultiplier tube (Hamamatsu). The area from which light was collected was restricted (unless otherwise noted) to the distal half of the apical dendrites (including part of stratum radiatum and all of stratum lacunosum/moleculare) by using four shutters that defined a rectangular area of interest. Slices were excited with 380 nm light for 500 ms/trial; bleaching was typically 0.3-0.5% per trial; background fluorescence was always <5% of total fluorescence and was not routinely subtracted. Calcium transients were measured as the ratio of the change in fluorescence (F) to the total fluorescence (F), or F/F (expressed as a percent). Transient waveforms are inverted (decreasing fluorescence upwards) for clarity. Electrical stimuli were delivered to the stratum oriens-alveus border above the loading site by using a monopolar tungsten electrode. Extracellular recordings were made with a glass pipette filled with ACSF. In some experiments this electrode also contained 50 µM tetrodotoxin and 5% fast green to monitor pressure injection. All other drugs were applied by bath perfusion (>3 ml/min.). Signals were digitized, stored and analyzed with Strathclyde ElectrophysiologySoftware (WCP version 1.6). Numerical values are expressed as mean ± SE.

Animals used in this study were maintained in strict accordance with guidelines approved by the Institutional Animal Care and Use Committee of the Medical College of Georgia.

	RESULTS

Abstract Introduction Methods Results Discussion References

In hippocampal pyramidal cells loaded with fura-2-AM, antidromic stimulation near the alveus-stratum oriens border in the presence of ionotropic receptor antagonists resulted in a transient decrease in fluorescence emission (380 nm excitation) from the distal half of the apical dendrites (see METHODS), consistent with a transient increase in intradendritic calcium. In a representative sample (n = 12) the 10-90% rise time of the fluorescence transient (F/F) was7.9 ± 0.3 ms and the transient decayed with a monoexponential timecourse of 76.2 ± 3.5 ms. The timecourse of these signals was similar to single action-potential-evoked calcium transients recorded from cortical pyramidal cell dendrites (Markram et al. 1995). Simultaneous field-potential recording from the region of the cell bodies (stratum pyramidale) indicated the dendritic calcium transient was preceded by an antidromic population action potential (n = 5; data not shown).

We then tested the susceptibility of dendritic calcium transients to inhibition by activation of G-protein-coupled receptors. Dendritic calcium transients were reversibly inhibited by activation of adenosine receptors (100 µM adenosine, 19 ± 3% inhibition, n = 6), serotonin receptors (30 µM serotonin, 17 ± 3%, n = 5), and GABA_B receptors (10 µM baclofen, 22 ± 2%, n = 7) (Fig. 1A). These agonists all activate receptors known to couple to G_i proteins and all hyperpolarize pyramidal neurons by activating a common pool of K⁺ channels (Nicoll et al. 1990). Application of a combination of all three of these agonists inhibited calcium influx by approximately the same amount as application of a single agonist (n = 3, data not shown). For comparison, we tested the effect of activation of metabotropic glutamate receptors (mGluRs) on dendritic calcium influx. Activation of mGluRs inhibits calcium channels in CA1 pyramidal neurons (Swartz 1993), but does not activate K⁺ channels in these cells. The selective mGluR agonist trans-(±)-1-amino-1,3-cyclopentanedicarboxyic acid (100 µM, trans-ACPD) reversibly inhibited dendritic calcium transients by 43 ± 3% (n = 6). In addition to inhibiting the calcium transient, trans-ACPD also reversibly decreased the total fluorescence (F) by ~5-7%, consistent with a increase in dendritic calcium (Jaffe and Brown 1994). The other agonists studied here had no effect on resting dendritic calcium (data not shown).

View larger version (9K): [in this window] [in a new window]   View larger version (21K): [in this window] [in a new window]   FIG. 1. A: inhibition of dendritic calcium influx by various agonists at G-protein-coupled receptors. Left: fluorescence transients (F/F, inverted such that increasing calcium is up) recorded from pyramidal cell dendrites after antidromic activation under control conditions, in the presence of 100 µM adenosine and after recovery superimposed. Middle: fluorescence transients recorded in the presence of 30 µM serotonin and after recovery superimposed. Right: fluorescence transient in the presence of 10 µM baclofen and after recovery superimposed. B: adenosine inhibits calcium influx by the same amount before and after block of T- and R-type calcium channels with Ni2+. Normalized absolute F/F is plotted vs. time; each point represents the mean of 7 identical experiments, every 5th point represents the mean ± SE. Adenosine (100 µM) and Ni2+ (50 µM) were applied where indicated.

To test the hypothesis that the presence of low-threshold, T-type Ca²⁺ channels on pyramidal neuron dendrites would influence the inhibition of calcium influx by activation on G-protein-coupled receptors, we measured inhibition of calcium transients by adenosine before and after block of these channels with 50 µM Ni²⁺. Low-threshold Ca²⁺ channels are reportedly more sensitive to Ni²⁺ than most high-threshold channels, including those that are inhibited by G-proteins (Bean 1989; Mogul and Fox 1991). If calcium influx through T-type channels was unaffected or increased by adenosine, we reasoned that the inhibition of dendritic calcium transients would be greater after these channels were blocked. However, in seven experiments adenosine inhibited dendritic calcium transients by the same amount before (27 ± 2%) and after (30 ± 2%) application of Ni²⁺ (P > 0.05, paired t-test; Fig. 1B). In these experiments Ni²⁺ inhibited calcium transients by 26 ± 2%, an amount consistent with previous reports of Ni²⁺-sensitive calcium influx in pyramidal neuron dendrites (Christie et al. 1995). Inhibition of calcium influx by Ni²⁺ was partly or completely reversible (Fig. 1B).

We then wanted to determine if any of the inhibition of calcium influx we observed was the result of inhibition of action-potential propagation into the dendritic tree. In particular, we predicted that receptors that activated inwardly rectifying K⁺ channels and hyperpolarized neurons (such as adenosine A₁ receptors) would inhibit action potential propagation, whereas those that depolarized neurons (such as mGluRs) would not. We assessed action-potential propagation into the dendrites of pyramidal neurons by recordingpopulation action potentials extracellularly in stratum radiatumor stratum lacunosum/moleculare. These biphasic potentials consist of an early positive phase, representing action-potential generation near the cell body layer and a late negative phase, representing active propagation of action potentials into the dendrites (Richardson et al. 1987; Turner et al. 1989). Therefore, manipulations that decrease action-potential propagation into dendrites, but not action-potential generation in the cell bodies, decrease the ratio of the negative to positive components (N/P ratio). This interpretation was confirmed by pressure applying tetrodotoxin (TTX; 50 µM) from the recording pipette (located at the stratum radiatum-stratum lacunosum/moleculare border) to selectively block distal dendritic sodium channels. Small applications decreased the negative component without affecting the positive component (n = 6; Fig. 2A1), as previously reported(Turner et al. 1989); this effect was slowly reversible. Larger applications completely abolished the negative component, although the positive component was also usually inhibited (~25%), presumably because of TTX diffusion toward the cell bodies (data not shown). Similarly, a number of studies have shown that action-potential propagation into CA1 pyramidal neuron dendrites fails with high-frequency activation (Callaway and Ross 1995; Spruston et al. 1995). In every case (n = 7) repetitive antidromic stimulation generated population responses with N/P ratios that decreased dramatically during the train (Fig. 2A2), consistent with propagation failure.

View larger version (21K): [in this window] [in a new window]   FIG. 2. A1: field potentials evoked by antidromic activation recorded in distal dendrites consisted of a positive-negative biphasic wave. The negative component was selectively inhibited by pressure application of tetrodotoxin (TTX; 50 µM) from the recording electrode, consistent with the interpretation that this component represents active propagation of action potentials into distal dendrites. A2: high-frequency (50 Hz for 100 ms) antidromic activation evokes population responses (recorded in the distal dendrites) with progressively attenuated negative components, consistent with frequency-dependent failure of action-potential propagation. B: adenosine but not trans-ACPD (tACPD) inhibits action-potential propagation into distal dendrites. Field potentials recorded as in A are shown under control conditions, in the presence of 100 µM adenosine, after recovery, and in the presence of 100 µM trans-ACPD. Only adenosine inhibits the negative component. C: adenosine inhibition of dendritic action-potential propagation is limited to distal dendrites. Left: an experiment similar to that in B, except that recording electrode is placed in the middle of stratum radiatum. Adenosine slightly increases both positive and negative components, suggesting action-potential propagation to this point was unaffected. Right: recordings made in stratum lacunosum/moleculare in the same slice, demonstrating adenosine inhibition of action-potential propagation (negative component) in distal dendrites.

We then tested the effects of adenosine and trans-ACPD on propagation of action potentials into dendrites (Fig. 2B). When the recording electrode was placed at the border between stratum radiatum and stratum lacunosum/moleculare, adenosine produced a consistent reversible decrease in the N/P ratio (0.65 ± 0.04, control; 0.36 ± 0.06, adenosine;P < 0.05, paired t-test; n = 7). Adenosine also produced a small (~10%) but consistent increase in the amplitude of the positive component, possibly because of hyperpolarization of pyramidal neurons. In contrast, trans-ACPD did not change the N/P ratio (0.59 ± 0.06, control; 0.58 ± 0.06, trans-ACPD; P > 0.05, paired t-test; n = 4). Trans-ACPD did produce a small (~10%) decrease in the amplitudes of both the positive and negative components in three of four slices, possibly because of the depolarization of pyramidal cells (not shown). These results suggest that adenosine, but not trans-ACPD, inhibits propagation of action potentials into pyramidal neuron dendrites. The effect of adenosine on propagation was restricted to distal branches of pyramidal neuron dendrites, as the N/P ratio did not change if the recording electrode was placed in the middle of stratum radiatum (n = 3; Fig. 2C).

Finally, we reasoned that inhibition of action-potential propagation into distal dendrites by adenosine should increase inhibition of action-potential-evoked calcium transients in the these dendrites relative to that in the proximal dendrites or cell bodies. To test this possibility, calcium transients recorded from the cell bodies (stratum pyramidale), the proximal third of stratum radiatum, and the distal third of stratum radiatum and stratum lacunosum/moleculare were compared in the same slices. In four experiments adenosine inhibited calcium transients recorded from stratum pyramidale by 12 ± 2%, transients recorded from proximal stratum radiatum by 12 ± 1%, and transients recorded from distal stratum radiatum and stratum lacumosum/moleculare by 39 ± 3% (Fig. 3). Because trans-ACPD did not inhibit dendritic action-potential propagation, a similar difference would not be expected for trans-ACPD. Indeed, trans-ACPD inhibited calcium transients recorded in stratum pyramidale by 44 ± 6% (n = 3), which was comparable to the 43 ± 3% (n = 6) inhibition of transients recorded from stratum radiatum.

View larger version (9K): [in this window] [in a new window]   View larger version (16K): [in this window] [in a new window]   FIG. 3. Adenosine inhibits calcium influx in the distal dendrites to a greater extent than proximal dendrites or cell bodies. A: calcium transients recorded from region of neuronal cell bodies (pyramidale), proximal apical dendrites (proximal radiatum), and distal apical dendrites (distal radiatum/LM) under control conditions and in presence of 100 µM adenosine are shown superimposed. Vertical calibration bar, 2% F/F stratum pyramidale, proximal stratum radiatum, 1% F/F distal stratum radiatum/lacunosum-moleculare. B: grouped data from 4 experiments identical to that shown in A. Bars showmean ± SE; open circles, individual data points. In every experiment adenosine inhibited calcium influx in distal dendrites much more than in cell bodies or proximal dendrites.

	DISCUSSION

Abstract Introduction Methods Results Discussion References

Single-channel analysis suggests that a large proportion of the voltage-gated calcium channels present on the distal apical dendrites of CA1 pyramidal cells are of the low-threshold T-type, and high-threshold R-type (Magee and Johnston 1995). These channels share two properties that distinguish them from many other voltage-gated calcium channels: they are relatively sensitive to block by Ni²⁺ ions (Bean 1989; Magee and Johnston 1995; Zhang et al. 1993) and they are relatively resistant to inhibition by activation of pertussis toxin-sensitive G-proteins (G_i/G_o proteins) (Bean 1989; Guyon and Leresche 1995; Hille 1994; Toth et al. 1996). The latter property suggests that the calcium channels on dendrites might be less sensitive to activation of various G-protein-coupled receptors than those on cell bodies or presynaptic terminals. Because many G_i-coupled receptors that inhibit Ca²⁺ channels also activate inwardly rectifying K⁺ channels, the resulting hyperpolarization could deinactivate T-type channels on dendrites, possibly increasing calcium influx mediated by these channels.

The present experiments were designed to empirically measure inhibition of single action-potential-evoked calcium influx by activation of G-protein-coupled receptors in intact neurons. The methods used were sufficiently sensitive to measure changes in calcium transients evoked by single action potentials and propagation of these action potentials throughout the entire dendritic tree. We found that activation of several G-protein-coupled receptors inhibited dendritic calcium influx. For example, adenosine, which inhibits voltage-gated calcium channels in pyramidal cell bodies by activating A₁ receptors (Mogul et al. 1993; Swartz 1993) and activates K⁺ channels in these cells (reviewed by Nicoll et al. 1990) inhibited calcium influx into pyramidal cell dendrites. However, the amount of inhibition was the same in the absence and presence of Ni²⁺ at a concentration that preferentially blocks T- and R-type channels. The result suggests that G-protein-mediated inhibition of net calcium influx into dendrites is not dampened by the presence of Ni²⁺-sensitive calcium channels, as might have been predicted.

In addition to inhibiting dendritic calcium influx, we found that activation of G-proteins also inhibited propagation of action potentials into the dendritic tree. Although no direct evidence is available, it is likely that either the hyperpolarization or increase in membrane conductance (and the resulting shunt) produced by opening of G-protein-coupled K⁺ channels accounts for this inhibition. The proposed role of hyperpolarization is consistent with the observations that direct hyperpolarization of pyramidal cells can inhibit propagation of single action potentials into distal dendrites (Tsubokawa and Ross 1996) and that depolarizing pyramidal neurons by increasing the bath concentration of K⁺ reverses the effect of adenosine on propagation (n = 3, data not shown). Also consistent with this idea is the observation that trans-ACPD, which does not activate these channels, does not inhibit propagation. Inhibition of propagation was limited to the most distal dendrites, those in distal stratum radiatum and stratum lacunosum/moleculare, similar to the effects of direct hyperpolarization (Tsubokawa and Ross 1996). One possible mechanism for this effect is that hyperpolarization deinactivates A-type voltage-gated K⁺ channels, which are abundant on CA1 pyramidal neuron dendrites and are capable of attenuating propagating action potentials (Hoffman et al. 1997). Alternative mechanisms include direct effects on dendritic voltage-gated K⁺ or Na⁺ channels (Jan and Jan 1997).

Failure to propagate likely contributed to inhibition of calcium influx in distal dendrites, as evidenced by the magnitude of the inhibition there compared with proximal or distaldendrites. Because adenosine inhibited calcium influx in dendritic regions that were reliably invaded and because trans-ACPD inhibited calcium influx without inhibiting propagation (even in distal dendrites), it is likely that some of the decreased calcium influx was the result of direct inhibition of calcium channels, as occurs in cell bodies and terminals. This conclusion is supported by the recent demonstration of G-protein-mediated inhibition of voltage-gated calcium currents in isolated (presumably proximal) dendritic segments (Kavalali et al. 1997). It should be pointed out that the magnitude of G-protein-mediated inhibition of somatic and proximal dendritic calcium influx observed here was not well predicted by voltage-clamp recordings. For example, adenosine inhibited somatic and proximal dendritic calcium influx by only 12%, compared with 32 and 45% inhibition of somatic and dendritic calcium currents, respectively (Kavalali et al. 1997; Swartz 1993). On the other hand, inhibition of calcium influx by trans-ACPD was greater than would have been predicted from voltage-clamp recordings (e.g., Kavalali et al. 1997).

In summary, despite the presence of Ni²⁺-sensitive T- and R-type calcium channels on CA1 pyramidal cell dendrites (Magee and Johnston 1995), activation of G-protein-coupled receptors that also couple to K⁺ channels inhibits calcium influx in these processes. At least two mechanisms contribute to this inhibition, inhibition of action-potential propagation and a more direct mechanism, most likely direct inhibition of calcium channels. The relative importance of these two mechanisms for activity-dependent regulation of dendritic calcium will likely depend on the circumstances. For example, because the inhibition of propagation apparently depends on membrane hyperpolarization, this mechanism would be effective only on dendritic branches other than those that receive the synaptic excitation that brings the soma to threshold (see also Tsubokawa and Ross 1996). In contrast, activation of mGluRs would inhibit calcium influx in dendritic branches that are receiving synaptic excitation. Pyramidal neuron dendrites possess a wide variety ofG-protein-coupled receptors that couple to calcium and potassium channels (Nicoll et al. 1990). It is therefore likely that these neurons use these receptors to regulate dendritic calcium influx and thus the multiple physiological consequences of this influx.

	ACKNOWLEDGEMENTS

  We thank J. Dempster for providing WCP.

  This work was supported by National Institute of Neurological Disorders and Stroke Grant NS-36455 and by a Veterans Affairs Merit Review.

	FOOTNOTES

  Address reprint requests to N. A. Lambert.

  Received 19 June 1997; accepted in final form 9 September 1997.

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