Low dose of dopamine may stimulate prolactin secretion by increasing fast potassium currents

Abstract

Dopamine (DA) released from the hypothalamus tonically inhibits pituitary lactotrophs. DA (at micromolar concentration) opens potassium channels, hyperpolarizing the lactotrophs and thus preventing the calcium influx that triggers prolactin hormone release. Surprisingly, at concentrations approximately 1000 lower, DA can stimulate prolactin secretion. Here, we investigated whether an increase in a K+ current could mediate this stimulatory effect. We considered the fast K+ currents flowing through large-conductance BK channels and through A-type channels. We developed a minimal lactotroph model to investigate the effects of these two currents. Both IBK and IA could transform the electrical pattern of activity from spiking to bursting, but through distinct mechanisms. IBK always increased the intracellular Ca2+ concentration, while IA could either increase or decrease it. Thus, the stimulatory effects of DA could be mediated by a fast K+ conductance which converts tonically spiking cells to bursters. In addition, the study illustrates that

Figure 1

Activation and inactivation functions of the voltage-dependent K⁺ currents. Thick black curve: activation of I_K (n_∞). Thin curve: activation of I_BK (f_∞). Dashed curves: activation and inactivation of I_A (a_∞, h_∞). Both I_BK and I_A turn on at lower voltages than I_K.

Figure 2

Effect of I_BK on spike pattern, intracellular Ca²⁺ concentration and PRL release. For g_BK=0 (A), the lactotroph model is spiking, [Ca] and PRL levels are above 0. Adding a small amount of BK conductance (B, g_BK=0.2 nS) does not change the spike pattern but moderately increases [Ca] and PRL levels. These levels increase more significantly when the pattern switches to bursting (C, g_BK=0.4 nS). In B and C, dotted lines represent the mean value, dashed lines represent mean value for g_BK=0.

Figure 3

Effects of I_BK on the fast subsystem bifurcation diagrams and the full system trajectory. A, k_c=0.16 ms⁻¹. Increasing g_BK moves the periodic branch to the right and initiates bursting. Arrows indicate direction of motion. B, k_c=0.1 ms⁻¹. The bifurcation diagrams are identical to A, but increasing g_BK does not lead to bursting and the trajectory moves only slightly to the right. In all panels, the z-shaped curve indicate the steady state of the system with [Ca] frozen (thick: stable; thin: unstable) and the ε-shaped curve indicate the minimum and maximum of periodic orbits (solid: stable; dashed: unstable). The dot-dashed curve is the [Ca]-nullcline. Above this curve d[Ca]/dt > 0 and below the curve d[Ca]/dt < 0. LK, low knee; HK, high knee; HB, Hopf bifurcation; HC, homoclinic bifurcation.

Figure 4

Summary of the effects of I_BK on the lactotroph model. A, two-parameter bifurcation diagram. The diagram shows how the position of LK, HK, HB and HC (cf. Figure 3) vary with g_BK. The main feature is that HB and HC move to the right when g_BK is increased, creating a region of bistability for g_BK > 0.2 nS. Horizontal bars represent the [Ca] variations during spiking or bursting of the model for various g_BK and k_c=0.16. B, when k_c is reduced to 0.1 ms⁻¹ bursting occurs at a higher value of g_BK. C, Effect of g_BK on the mean [Ca] for both values of k_c. Arrows indicate the onset of bursting (closed, blue: k_c=0.16; open, red: k_c=0.1 ms⁻¹).

Figure 5

Effect of I_A on spike pattern, intracellular Ca²⁺ concentration and PRL release. A, g_A=0, same as Figure 2A, showing the spiking regime and basal [Ca] and PRL levels. B, adding a small amount of A-type conductance (g_A = 8 nS) initiates bursting and increases [Ca] and PRL levels. C, a higher conductance (g_A = 25 nS) further increases burst duration but average [Ca] and PRL begin to decrease. In B and C, dotted lines represent the mean value, dashed lines represent mean value for g_A=0.

Figure 6

Effects of I_A on the fast subsystem bifurcation diagrams and the full system trajectory. A, k_c=0.16 ms⁻¹. Increasing g_A moves the low knee to the left, i.e. towards higher [Ca]. Left panel, spiking trajectory, same as Fig 3A left. Middle panel, a bursting trajectory exists despite the lack of a bistability region between lower and upper branches. Most of the spiking branch is unstable. However, stable bursting and chaotic solutions coexist with the unstable periodic branch (not shown). Right panel, the bursting trajectory encompasses (and slightly overshoots) the bistability region. B, k_c=0.1 ms⁻¹. The bifurcation diagrams are identical to A, but the trajectories are restricted to narrower [Ca] ranges in the middle and right panels.

Figure 7

Effect of increasing the [Ca] time constant on the bursting pattern. A, g_A = 25 nS, decreasing f_c slows down the bursts as expected for “classical” bursting. B, g_A = 8 nS, decreasing f_c has practically no effect on the burst pattern. The vertical dashed lines indicate the time when f_c was changed.

Figure 8

Summary of the effects of I_A on the lactotroph model. A, two-parameter bifurcation diagram. As g_A is increased, the LK is moved to the left, creating a region of bistability for g_A > 9 nS. Horizontal bars represent the [Ca] variations during spiking or bursting for various g_A and k_c=0.16. B, same for k_c=0.1 ms⁻¹. C, Average [Ca] over a range of values of g_A. Arrows indicate the onset of bursting (closed, blue: k_c=0.16; open, red: k_c=0.1 ms⁻¹). For k_c=0.16 <Ca> first increases with g_A and then decreases as a bistability range is created and the trajectory extends to lower [Ca] values.