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J. Biol. Chem., Vol. 275, Issue 34, 26220-26224, August 25, 2000

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Calmodulin Directly Gates Gap Junction Channels^*

Camillo Peracchia, Anna Sotkis, Xiao G. Wang, Lillian L. Peracchia, and Anthony Persechini

From the Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York 14642-8711

Received for publication, May 10, 2000, and in revised form, June 12, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Cytosolic changes control gap junction channel gating via poorly understood mechanisms. In the past two decades calmodulin participation in gating has been suggested, but compelling evidence for it has been lacking. Here we show that calmodulin indeed is associated with gap junctions and plays a direct role in chemical gating. Expression of a calmodulin mutant with the N-terminal EF hand pair replaced by a copy of the C-terminal pair dramatically increases the chemical gating sensitivity of gap junction channels composed of connexin 32 and decreases their sensitivity to transjunctional voltage. The increased chemical gating sensitivity, most likely because of the higher overall Ca²⁺ binding affinity of this mutant as compared with native calmodulin, and the decreased voltage sensitivity are only observed when the mutant is expressed before connexin 32. This indicates that the mutant, and by extension native calmodulin, must interact with connexin 32 before gap junctions are formed. Immunofluorescence data suggest further that this interaction leads to incorporation of native or mutant calmodulin into the connexon as an integral regulatory subunit.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The permeability of gap junction channels is regulated by changes in the composition of the cytosol (1). As channels close, cells uncouple from each other electrically and metabolically. Uncoupling is mainly a protective mechanism, but evidence for channel gating sensitivity to nearly physiological [Ca²⁺]_i (2) suggests that it also participates in normal cellular functions. Although a number of uncoupling agents have been identified, little is known on channel gating mechanisms (3, 4).

Cytosolic calcium (5) and hydrogen (6-8) ions are believed to play a role in gap junction regulation, but it is still unclear whether they act independently and whether their effect is direct or mediated by cytosolic components (4). We have reported a closer correlation of junctional conductance (G_j) with [Ca²⁺]_i than with [H⁺]_i and have proposed that Ca²⁺ mediates the effect of lowered pH_i (2, 9-12). The relative insensitivity of coupling to acidification alone was recently confirmed in astrocytes subjected to ischemia (13). In Novikoff hepatoma cells (11, 14) and Xenopus oocytes (12) G_j was affected by nanomolar [Ca²⁺]_i. This has been confirmed in a number of other cell types (15-18).

Two decades ago, evidence for the ability of a nonspecific calmodulin (CaM)¹ antagonist (trifluoperazine) to prevent CO₂-induced uncoupling of Xenopus embryonic cells suggested that CaM may participate in channel gating (19, 20). This hypothesis was strengthened by evidence for CaM binding to connexin 32 (Cx32) in gel overlays (21, 22). Subsequently, more specific CaM blockers (calmidazolium and W7) were observed to prevented uncoupling in various cell types (23, 24). Recently, CaM participation in gap junction channel gating has also been suggested by evidence that inhibition of CaM expression eliminates CO₂-induced gating (12) and by the demonstration that a fluorescent CaM derivative binds to Cx32 and Cx32 fragments in vitro (25). Consistent with this view are also data from Cx32 mutants expressed heterotypically with Cx32wt in oocytes and tested in the presence and absence of CaM (26). The behavior of these mutants demonstrated the function of a slow gate sensitive to both CO₂ and transjunctional voltage (V_j) and suggested that the chemical gate and the slow gate are the same, and likely to be a sizable negatively charged particle (2, 26). The slow kinetics of the chemical gate was demonstrated in single channel records (27). With inhibition of CaM expression, slow gating and CO₂-sensitive gating virtually disappeared (2), suggesting CaM participation in this mechanism.

To question more directly whether CaM participates in chemical gating, we have monitored the effects of expressed CaM mutants on chemical and V_j gating of homotypic Cx32 channels and have investigated whether CaM is localized at gap junctions using immunofluorescence microscopy. Cx32 is widely expressed in mammalian tissues, and Cx32 mutations are involved in the pathogenesis of the X-linked Charcot-Marie-Tooth demyelinating disease (3, 28). Two CaM mutants (29) were used in this study: CaMCC and CaMNN. In CaMCC, the N-terminal EF hand pair (residues 9-75) is replaced by a duplication of the C-terminal pair (residues 82-148), whereas in CaMNN the C-terminal pair is replaced with the N-terminal pair. These CaM mutants were selected based on the fact that the two lobes exhibit considerable functional specialization. Because the Ca²⁺ affinity constant of the C-terminal EF hand pair is almost 1 order of magnitude greater than that of the N-terminal pair (29), we felt that at the very least the greater overall Ca²⁺ binding affinity of CaMCC might translate into significantly increased chemical gating sensitivity of gap junction channels.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Oocyte Preparation and Microinjection-- Oocytes were prepared as described previously (12). Briefly, adult female Xenopus laevis frogs were anesthetized with 0.3% tricaine (MS-222), and the oocytes were surgically removed from the abdominal incision. The oocytes were placed in ND96 solution containing 96 mM NaCl, 2 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 5 mM HEPES (pH 7.6 with NaOH). Oocytes at stage V or VI were subsequently defolliculated for 80 min at room temperature in 2 mg/ml collagenase (Sigma) in a nominally calcium-free solution (OR2) containing 82.5 mM NaCl, 2 mM KCl, 1 mM MgCl₂, 5 mM HEPES (pH 7.6 with NaOH). Defolliculated oocytes were first injected with antisense oligonucleotide complementary to endogenous Xenopus Cx38 (26). The antisense oligonucleotide blocks completely the endogenous junctional communication. On the next day, the oocytes were injected at the vegetal pole with cRNA of CaM mutants, CaMCC, or CaMNN and incubated overnight at 18 °C. They were reinjected 24 h later with Cx32 cRNA, homotypically paired 7-24 h later, following mechanical stripping of their vitelline layer in a hypertonic medium and superfused at a flow rate of 0.6 ml/min by a peristaltic pump (Rainin Instrument Co. Inc., Woburn, MA) with either ND96 or OR2 containing 180 µM BAPTA.

Electrophysiology and Calcium Measurement-- Oocyte pairs were studied electrophysiologically 0.5-2 h after pairing using the standard double voltage clamp procedure for measuring G_j (8). Following the insertion of a current and a voltage microelectrode in each oocyte, both oocytes were initially voltage clamped individually with two oocyte clamp amplifiers (OC-725C, Warner Instrument Corp., Hamden, CT) to the same holding potential, V_m1 = V_m2 (usually 20 mV), so that no junctional current would flow at rest (I_j = 0). A V_j gradient was created by imposing a +20 mV voltage step (V₁) of 2-s duration every 10 or 30 s to oocyte 1 while maintaining V₂ at V_m, thus V_j = V₁. The negative feedback current (I₂), injected by the clamp amplifier in oocyte 2 for maintaining V₂ constant at V_m, was used for calculating G_j, as it is identical in magnitude to the junctional current (I_j), but of opposite sign (I_j = I₂); G_j = I_j/V_j. Pulse generation and data acquisition were performed by means Clampex 8.0 software (Axon Instruments, Inc., Foster City, CA) and DigiData 1200 interface (Axon). I_j and V_j were measured with Clampfit 8.0 (Axon), and the data were plotted with SigmaPlot version 5.0 (SPSS Inc., Chicago, IL).

For studying voltage dependence of G_j, each oocyte of the pair was first voltage clamped at 20 mV. Voltage steps of 20 mV (± 120 mV maximum) and 25-s duration were then applied every 45 s to either oocyte of the pair while maintaining the other at 20 mV. To illustrate the relationship between steady-state G_j (G_{j ss}) and V_j, the normalized G_j (G_j ss/G_j max) was plotted with respect to V_j. The curve was fitted to a two-state Boltzmann's distribution of the form: (G_j ss  G_j min)/(G_j max  G_j ss) = exp[A(V_j  V₀)], where V₀ is the V_j value at which the voltage-sensitive conductance is one half the maximal value, and G_j min is the theoretical minimum normalized G_j. A = q/kT is a constant expressing voltage sensitivity in terms of number of equivalent gating charges, , moving through the entire applied field, where q is the electron charge, k is the Boltzmann constant, and T is the temperature (K).

For monitoring changes in cytosolic Ca²⁺, oocytes were injected with a solution of Calcium Green-1 (C-3010, Molecular Probes Inc., Eugene, OR) to reach a calculated intra-oocyte concentration of ~100 µM. The oocytes were viewed 1-3 h later with a Nikon inverted microscope coupled to a Ca²⁺ imaging apparatus (InCyt Im^TM, Intracellular Imaging Inc., Cincinnati, OH), focusing on the bottom oocyte surface.

Immunofluorescence-- Immunofluorescence labeling of CaM and Cx32 was performed on cultured HeLa cells transfected with Cx32 wild type. The cells were fixed with 4% formaldehyde for 30 min at room temperature or with 100% methanol for 5 min at 4 °C. Coverslips with dried cells were permeabilized for 2 h in 0.1 M phosphate buffer containing 0.3% Triton X-100 and 10% goat serum (PBTGS). Between steps involving antibodies, the preparations were washed three times for 5 min each with PBTGS. The cells were double-labeled, and all the antibodies were diluted in PBTGS. The preparations were first incubated overnight with polyclonal primary antibody to CaM (1:100- 1:1000, Zymed Laboratories Inc., San Francisco, CA), followed by 1 h of incubation with a secondary goat anti-rabbit antibody coupled to Alexa488 (1:500, Molecular Probes Inc.). The cells were then incubated overnight with monoclonal primary antibody to Cx32 (1:100-1:1000, Zymed Laboratories Inc.), followed by 1 h of incubation with a secondary anti-mouse antibody coupled to Cy-3 (1:500, Accurate Inc., Westbury, NY). The preparations were allowed to air-dry and were mounted on slides using an anti-fade mounting medium. Cells were observed under a Nikon Microphot fluorescence microscope fitted with a Hamamatsu C4742-95 cooled CCD video camera. Images were collected in a laboratory computer using Image-pro (Meyer Instruments, Inc, Houston, TX).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

In oocytes expressing CaMCC, the initial G_j, measured 0.5-2 h after pairing, is very low (G_j = 0.08 ± 0.1 µS, n = 21) compared with controls (homotypic Cx32 channels without CaMCC; G_j = 5.44 ± 4.9 µS, n = 43), because most channels are in closed state. Indeed, G_j increases to 0.85 ± 0.8 µS (n = 21) when [Ca²⁺]_i, monitored with Calcium Green-1, is lowered by superfusing the oocytes with 180 µM BAPTA in nominally calcium-free solutions (Fig. 1A). With return to normal external saline, G_j drops rapidly at first and then very slowly, remaining at higher than initial values for long periods of time (Fig. 1A), presumably because the oocytes are still depleted in Ca²⁺. Superfusion with nominally calcium-free solutions with a lower BAPTA concentration (90 µM) are significantly less effective (Fig. 1B). This suggests that CaMCC drastically increases the sensitivity of the chemical gate, such that the cell-cell channels are closed even at resting [Ca²⁺]_i while they are normally observed to be open.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Effect of CaMCC on the chemical gating sensitivity of Cx32 gap junction channels. In Xenopus oocytes expressing CaMCC before Cx32, Gj is very low (Gj = 0.08 ± 0.1 µS, n = 21; A). Superfusion with 180 µM BAPTA in nominally calcium-free solutions lowers [Ca2+]i (monitored with Calcium Green-1; A) and increases Gj to 0.85 ± 0.8 µS (n = 21; A). Lower BAPTA concentrations (90 µM) are significantly less effective (B). Cx32 channels expressed after CaMCC are much more sensitive to CO2 than controls (C). With 3 min of superfusion (0.6 ml/min) of solutions gassed with 100% CO2, Gj drops to zero at a maximum rate of 30-40%/min (C), whereas in controls it decreases by only 15 ± 5% at a maximum rate of ~9%/min (C). After CO2 washout, Gj remains at 0 µS for a long time but increases rapidly with BAPTA (180 µM) superfusion (C). Expression of CaMNN or expression of Cx32 before CaMCC has no effect on chemical gating, as with a 15-min exposures to 100% CO2 Gj decreases, as in controls, by only 40-50% (D). This suggests that CaMCC must be present in the oocyte when Cx32 is being synthesized and/or assembled in the connexon. Thus, CaM is likely to be an integral subunit of the connexon.

The increase in chemical gating sensitivity associated with expression of CaMCC was further confirmed by testing the effects of CO₂ in normal saline solutions several minutes after the BAPTA superfusion. We have previously shown that exposure to CO₂ increases both [H⁺]_i and [Ca²⁺]_i, but G_j correlates more closely with the latter, suggesting that Ca²⁺ mediates the effect of lowered pH_i (9-12). With 3 min of superfusion of normal saline gassed with 100% CO₂, G_j rapidly drops to 0 (Fig. 1C), whereas in control experiments (Fig. 1C) it decreases only by 15 ± 5% (n = 7). After CO₂ washout, the channels remain closed for a long time but readily reopen with superfusion of 180 µM BAPTA in nominally calcium-free solutions (Fig. 1C). Significantly, the effect of CaMCC on gating is only observed when CaMCC is expressed before Cx32. Expression of Cx32 before CaMCC (Fig. 1D) or coexpression of CaMCC and Cx32 (data not shown) has no appreciable effect on gating sensitivity. No effect is also observed with expression of CaMNN (Fig. 1D) or overexpression of CaM (data not shown). These results suggest that CaMCC, and by extension native CaM, must be associated with Cx32 before it is assembled in the connexon. The simplest interpretation is that CaM is an integral, regulatory subunit of the connexon.

An intimate relationship between CaMCC and Cx32 is also suggested by the significant effect of CaMCC on V_j-gating sensitivity. Fig. 2 (A and B) presents a comparison of junctional currents (I_j) generated by subjecting oocyte pairs to families of 20 mV V_j steps (± 120 mV maximum, 25-s duration). In controls, Cx32 channels demonstrate a typical V_j sensitivity, characterized by drastic, exponential, I_j decay with time for V_js > ± 40 mV (Fig. 2A). In contrast, when CaMCC is expressed before Cx32, the channels show a significantly decreased V_j sensitivity, characterized by a reduction of I_j decay rate for V_j values of more than ±40 mV (Fig. 2B). Significantly, expression of CaMCC after Cx32 does not affect V_j sensitivity (Fig. 2C). The effect of CaMCC is readily demonstrated by plotting the relationship between normalized G_j (G_j ss/G_j max) and V_j, and fitting control and CaMCC data to a two-state Boltzmann's distribution (Fig. 2D). The Boltzmann values show that expression of CaMCC before Cx32 drastically decreases V_j sensitivity. G_j drops only by ~40% with V_j as high as ±120 mV, and the number of equivalent gating charges () moving through the applied field is halved (Fig. 2D). These data suggest that CaM must be closely associated with Cx32 channels, because V_j gating is an inherent property of the connexin.

View larger version (30K): [in this window] [in a new window]   Fig. 2.   Effect of CaMCC on the transjunctional voltage (Vj) gating sensitivity of gap junction channels composed of Cx32. A and B show a comparison of junctional currents (Ij) resulting from the application of families of 20 mV Vj steps (±120 mV maximum, 25-s duration). In controls, Cx32 channels show typical sensitivity to Vj, characterized by drastic, exponential, Ij decay with time for Vj values of more than ±40 mV (A). With CaMCC expressed before Cx32 the Ij decay with time for Vj values of more than ±40 mV is significantly reduced (B). Expression of CaMCC after Cx32 does not alter the Vj sensitivity (C). The effect of CaMCC on Vj sensitivity is obvious in plots of the relationship between normalized Gj (Gj ss/Gj max) and Vj (D). The Boltzmann values are: V0 = 60.6 mV,  = 2.4, and Gj min = 0.24 (n = 7) for control Cx32 channels (absence of CaMCC); V0 = 60.7 mV,  = 1.09, and Gj min = 0.58 (n = 7) for Cx32 channels expressed after CaMCC; and V0 = 64.5 mV,  = 2.4, and Gj min = 0.25 (n = 3) for Cx32 channels expressed before CaMCC. Thus, with CaMCC expressed before Cx32, Gj drops with Vj (±120 mV) by only ~40%, whereas with native CaM or with CaMCC expressed after Cx32 it drops by ~75% (D). In addition, with CaMCC expressed before Cx32 the number of equivalent gating charges () moving through the applied field is halved; note the sharply reduced steepness of the Boltzmann curve (D).

A close association between CaM and Cx32 is further demonstrated by immunofluorescence data from cultured HeLa cells expressing Cx32 (Fig. 3). Cells were fixed with formaldehyde or methanol, permeabilized with Triton X-100, sequentially exposed to monoclonal or polyclonal antibodies to Cx32 and CaM, and stained with anti-IgG antibodies tagged with two different fluorescent dyes. This procedure results in loss of soluble CaM, hence the lack of nuclear staining (Fig. 3). The immunofluorescence labeling shows that Cx32 and CaM colocalize in punctated or linear areas of cell-cell contact (Fig. 3), indicating a close spatial relationship between CaM and Cx32 gap junctions. Localization of fluorescent label at junctional sites is also observed in cells exposed to CaM antibodies alone (data not shown).

View larger version (53K): [in this window] [in a new window]   Fig. 3.   Immunofluorescence labeling of CaM and Cx32 in cultured HeLa cells expressing wild type Cx32. A and B show the individual distribution of CaM (green) and Cx32 (red), respectively. C shows a superposition of A and B. Cx32 and CaM colocalize in linear and punctated areas of cell-cell contact (region between arrowheads). Labeling for Cx32 and CaM is seen also in the cytoplasm, where the two proteins colocalize in punctated areas. These areas likely correspond to vesicular gap junctions retrieved from the plasma membrane, and/or to Cx32 in the Golgi apparatus. The same junctional and cytosolic Cx32 distribution was also observed in HeLa cells expressing Cx32 genetically linked to green fluorescent protein (data not shown).

Altogether these data indicate that CaM is intimately associated with connexin channels and participates as a regulatory subunit in channel gating. The drastic increase in chemical gating sensitivity of Cx32 channels containing CaMCC may be explained by the higher overall Ca²⁺ binding affinity of CaMCC, when compared with native CaM (29). Potential CaM binding sites have been identified in Cx32 (30): one at the N terminus (residues 15-32) and the other at the base of the C terminus (residues 209-221). However, mutation of basic residues to neutral or acidic residues at the C-terminal site, which should inhibit CaM binding, paradoxically resulted in increased chemical gating sensitivity (26, 31, 32). Thus, the N-terminal, rather than C-terminal, domain of Cx32 is likely to contain the CaM binding site. Significantly, the sequence of the N-terminal CaM-binding site is highly conserved among connexins and contains the binding motif identified in a class of CaM-dependent proteins that include CaM kinases I and II, MARCKS protein, synapsin, and the heat shock 84-kDa protein (reviewed in Ref. 33).

With an increase in [Ca²⁺]_i, CaM may physically block the channel (cork gating; Ref. 2) or close the channel via conformational changes in Cx32. CaM and the cytoplasmic mouth of the connexon have opposite charge characteristics, and both channel mouth and CaM lobes are ~25 Å in diameter (2); thus, if CaM were gating by obstructing the channel, a CaM lobe would fit in the channel mouth. Localization of CaM at the N terminus (residues 15-32) would place it in a strategic position for gating, because substituted cysteine accessibility method data suggest that the next two residues (Ile³³ and Met³⁴) are within the cytoplasmic mouth of the channel (34, 35).

It is now becoming apparent that CaM regulates the activities of a number of channel functions. The presence of CaM binding sites and/or the direct CaM participation in channel mechanisms have been reported for Ca²⁺-activated Na⁺ and K⁺ channels of Paramecium, the transient receptor potential like nonspecific Ca²⁺ channel of Drosophila melanogaster, the ryanodine receptor, the small conductance Ca²⁺-activated K⁺ channel, the calcium-dependent K⁺ channel, the L-type calcium channel, the P/Q-type calcium channel, and the voltage-dependent Na⁺ channel (36-44).

In conclusion, the data we have presented indicate that CaM is involved in chemical gating of gap junction channels made of Cx32 through a direct interaction with the connexin. The evidence includes the drastic increase in chemical gating sensitivity that is observed when the CaM mutant CaMCC is expressed before, but not after, Cx32, the effect of expressed CaMCC on transjunctional voltage gating, and the colocalization of CaM and Cx32 at junctional contacts.

	ACKNOWLEDGEMENTS

We are indebted to Drs. Peter Shrager and Katie Kazarinova Noyes for help with the immunofluorescence technique and for making available their fluorescence equipment.

	FOOTNOTES

^* This work was supported by National Institutes of Health Grant GM20113.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.

To whom correspondence should be addressed: Dept. of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave., Rochester, NY 14642-8711. Tel.: 716-275-2201; Fax: 716-273-2652; E-mail: camillo_peracchia@urmc.rochester.edu.

Published, JBC Papers in Press, June 13, 2000, DOI 10.1074/jbc.M004007200

	ABBREVIATIONS

The abbreviations used are: CaM, calmodulin; Cx32, connexin 32; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N',-tatraacetic acid.

	REFERENCES

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