TRPM4 links calcium signaling to membrane potential in pancreatic acinar cells
Gyula DiszháziZsuzsanna MagyarErika LisztesEdit Tóth‐MolnárPéter P. NánásiRudi VennekensBalázs I. TóthJános Almássy
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Abstract:
Transient receptor potential cation channel subfamily M member 4 (TRPM4) is a Ca2+-activated nonselective cation channel that mediates membrane depolarization. Although, a current with the hallmarks of a TRPM4-mediated current has been previously reported in pancreatic acinar cells (PACs), the role of TRPM4 in the regulation of acinar cell function has not yet been explored. In the present study, we identify this TRPM4 current and describe its role in context of Ca2+ signaling of PACs using pharmacological tools and TRPM4-deficient mice. We found a significant Ca2+-activated cation current in PACs that was sensitive to the TRPM4 inhibitors 9-phenanthrol and 4-chloro-2-[[2-(2-chlorophenoxy)acetyl]amino]benzoic acid (CBA). We demonstrated that the CBA-sensitive current was responsible for a Ca2+-dependent depolarization of PACs from a resting membrane potential of -44.4 ± 2.9 to -27.7 ± 3 mV. Furthermore, we showed that Ca2+ influx was higher in the TRPM4 KO- and CBA-treated PACs than in control cells. As hormone-induced repetitive Ca2+ transients partially rely on Ca2+ influx in PACs, the role of TRPM4 was also assessed on Ca2+ oscillations elicited by physiologically relevant concentrations of the cholecystokinin analog cerulein. These data show that the amplitude of Ca2+ signals was significantly higher in TRPM4 KO than in control PACs. Our results suggest that PACs are depolarized by TRPM4 currents to an extent that results in a significant reduction of the inward driving force for Ca2+. In conclusion, TRPM4 links intracellular Ca2+ signaling to membrane potential as a negative feedback regulator of Ca2+ entry in PACs.Keywords:
Calcium Signaling
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1. Membrane potential and input resistance measurements were made on segments of pancreas from mice or rats, whereas potential measurements alone were made on pancreas from cats or rabbits placed in a tissue bath which was perfused with a Krebs-Henseleit solution.2. The acinar cell membrane potential was about -40 mV and the input resistance 4-8 MOmega. Spontaneous miniature depolarization potentials were occasionally observed superimposed upon the resting potential. In these cases synchronous reductions in input resistance were observed.3. The immediate effect of stimulation with ACh was always a depolarization and a concomitant reduction in input resistance and time constant. In some cases a secondary depolarization was observed accompanied by an increase in input resistance. The time constant, however, remained as short as in the first phase of depolarization.4. In the rabbit pancreas ACh evoked biphasic potential changes: depolarization followed by hyperpolarization. A similar pattern could sometimes also be observed in the mouse pancreas following a brief pulse of ACh addition. In these cases the depolarization was followed by a small but relatively long lasting hyperpolarization. The depolarization was accompanied by a reduction in input resistance.5. Pancreozymin caused depolarization of the acinar cell membrane and a marked reduction in input resistance and time constant.6. In the presence of atropine (1.4 x 10(-6)M) depolarization of the acinar cell membrane by an elevated K concentration (50 mM) in the bathing fluid did not reduce the input resistance.7. It is concluded that the two physiological stimulants of pancreatic protein secretion, ACh and pancreozymin, act on the acinar cells by increasing the permeability of the plasma membrane.
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Electrical responses to brief electrical stimulation were investigated in the cerebral artery of a guinea-pig using a microelectrode. A single brief stimulus (0.05 ms) induced a spike potential followed by a depolarizing slow-potential, and these events were associated with muscle contraction. An outward current injected into the smooth muscle cell induced spike potential but failed to induce depolarizing slow-potential. These activities persisted in the presence of TTX (10(-6) M), guanethidine (5 X 10(-6) M), or atropin (10(-5) M). TEA (5 mM) enhanced the amplitude of the spike potential, but not that of the depolarizing slow-potential. When the external Na was reduced, the membrane transiently hyperpolarized. During this period, the depolarizing slow-potential could be evoked. In a Cl-deficient solution, the membrane depolarized and the amplitude of the depolarizing slow-potential decreased. From these observations it is believed that the contribution of K, Na, or Cl is minor. In a 20 mM-Ca solution, a brief stimulation induced neither spike potential nor depolarizing slow-potential, but did induce a hyperpolarizing slow-potential. The hyperpolarizing slow-potential was also induced in a Na-deficient solution, but only after completion of Na re-distribution across the membrane. These observations suggest that a substance released by brief stimulation produces a prolonged change in ionic conductances of the smooth muscle membrane, allowing the muscle to contract for a certain period.
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1. Two glass micro-electrodes were inserted into neighbouring cells from rat or mouse pancreatic segments, superfused in vitro. The tip of a third glass micro-electrode, filled with 2 M-AChCl, was placed just outside the acinus under investigation. Membrane potential and resistance, and changes in these parameters in response to short pulses of ACh stimulation, were recorded.2. The resting current-voltage relationship, obtained by injecting 100 msec depolarizing or hyperpolarizing current pulses through one of the intracellular micro-electrodes and recording the membrane potential with the other intracellular electrode, was linear within the range -5 to -60 mV.3. Injecting depolarizing or hyperpolarizing current (d.c.) through one of the intracellular micro-electrodes, the membrane potential (as measured with the other intracellular micro-electrode) could be set at various levels. The effect of ACh at different membrane potentials was investigated. When the acinar cell membrane was hyperpolarized, the amplitude of ACh-evoked depolarization was increased, while ACh-evoked depolarization was reduced when the membrane potential was reduced by depolarizing current, and finally changed into a hyperpolarization at very low membrane potentials. In each acinus investigated (rat and mouse), there was a linear relationship between amplitude of ACh-evoked potential change (DeltaV) (+ value or - value according to polarity) and resting membrane potential. During superfusion with control solution, the value of the membrane potential at which ACh did not evoke a potential change (E(ACh)) was about -15 mV in the mouse and about -20 mV in the rat. During superfusion with a chloride-free sulphate-containing solution (steady state), a linear relationship between DeltaV and resting membrane potential was again found but E(ACh) (mouse) was about +10 mV.4. A continuous rough estimate of E(ACh) was obtained by injecting repetitively depolarizing current pulses (100 msec) through one intracellular micro-electrode; in this way, the effect of ACh measured by the other intracellular electrode could be assessed simultaneously at the spontaneous resting level, and at a depolarized level. The direction of change in E(ACh) following acute changes in the superfusion fluid ion composition was assessed. Replacing extracellular chloride by sulphate caused an immediate change in E(ACh) in the positive direction. Re-admission of chloride, after a long period of chloride ion deprivation, caused an immediate sharp change in E(ACh) in the negative direction. Replacing extracellular sodium by Tris caused an immediate transient negative change in E(ACh). In contrast, taking away extracellular calcium changed E(ACh) in a positive direction. Augmenting extracellular potassium concentration to 40 mM caused a change in E(ACh) in the positive direction.5. At a membrane potential (V) equal to E(ACh) the sum of ionic currents evoked by the action of ACh is zero. Using the Goldman treatment, it appears that ACh increases membrane Na, K and Cl permeability. The approximate relative ion permeabilities of the pathways opened up by ACh are: P(Na)/P(K) = 2.5 and P(Cl)/P(K) = 5. At V = E(ACh), the approximate relative sizes of the ACh-evoked currents are: I(Na)/I(K) = 2.6 and I(Cl)/I(K) = 1.6 ACh, therefore, causes influx of Na and Cl and a small efflux of K.
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The euryhaline charophyte Lamprothamnium papulosum has the ability to reduce the extracellular electron acceptor ferricyanide (Fe3+Cy). Addition of 0.5 mol m−3 Fe3+Cy stimulated H+-efflux at a rate of 0.8 H+/Fe3+Cy-reduced and increased K+-efflux into a potassium-free medium at a rate of 0.66 K+/Fe3+Cy-reduced. 0.5 mol m−3 Fe3+Cy-induced maximum membrane depolarization for cells with resting potentials more negative than the diffusion potential. The peak value of Fe3+Cy-induced depolarizations was similar to the potential obtained by poisoning the electrogenic pump with DCCD. The value of maximum depolarization was determined by (K+)0. Em tended to more positive values with increasing (K+)0. Depolarizations coincided with a decrease in membrane resistance (Rm) from a resting value of 1.5 Ωm2 to 0.2 Ω m2 in the depolarized state. Depolarization increased the sensitivity of the membrane potential (Em) to (K+)0. The resting potential was only slightly changed when (K+)0 was increased from 3 to 15 mol m−3. The Fe3+ Cy-induced depolarized Em changed in a Nernstian fashion when (K+)0 was increased. It is concluded that Fe3+Cy reduction causes a net depolarization current flow across the plasmalemma. The depolarization shifts the membrane from a hyperpolarized pump dominated state into a depolarized K+ diffusion state.
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