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There are two contradictory explanations for central respiratory rhythmogenesis. One suggests that respiratory rhythm emerges from interaction between inspiratory and expiratory neural semicenters that inhibit each other and thereby provide reciprocal rhythmic activity (Brown 1914). The other uses bursting pacemaker activity of individual neurons to produce the rhythm (Feldman and Cleland 1982). Hybrid models have been developed to reconcile these two seemingly conflicting mechanisms (Smith et al. 2000; Rybak et al. 2001). Here we report computer simulations that demonstrate a unified mechanism of the two types of oscillator. In the model, we use the interaction of Ca[sup ++]-dependent K[sup +] channels (Mifflin et al. 1985) with Ca[sup ++]-induced Ca[sup ++] release from intracellular stores (McPherson and Campbell 1993), which was recently revealed in neurons (Hernandez-Cruz et al. 1997; Mitra and Slaughter 2002a,b; Scornik et al. 2001). Our computations demonstrate that uncoupled neurons with these intracellular mechanisms show conditional pacemaker properties (Butera et al. 1999) when exposed to steady excitatory inputs. Adding weak inhibitory synapses (based on increased K[sup +] conductivity) between two model neural pools surprisingly synchronizes the activity of both neural pools. As inhibitory synaptic connections between the two pools increase from zero to higher values, the model produces first dissociated pacemaker activity of individual neurons, then periodic synchronous bursts of all neurons (inspiratory and expiratory), and finally reciprocal rhythmic activity of the neural pools. [ABSTRACT FROM AUTHOR]

Mg[sup 2+], an important constituent of the intracellular milieu in cardiac myocytes, is known to inhibit ryanodine receptor (RyR) Ca[sup 2+] release channels by competing with Ca[sup 2+] at the cytosolic activation sites of the channel. However, the significance of this competition for local, dynamic Ca[sup 2+]-signaling processes thought to govern cardiac excitation-contraction (EC) coupling remains largely unknown. In the present study, Ca[sup 2+] stimuli of different waveforms (i.e., sustained and brief) were generated by photolysis of the caged Ca[sup 2+] compound nitrophenyl (NP)-EGTA. The evoked RyR activity was measured in planar lipid bilayers in the presence of 0.6-1.3 mM free Mg[sup 2+] at the background of 3 mM total ATP in the presence or absence of i mM luminal Ca[sup 2+]. Mg[sup 2+] dramatically slowed the rate of activation of RyRs in response to sustained (≥10-ms) elevations in Ca[sup 2+] concentration. Paradoxically, Mg[sup 2+] had no measurable impact on the kinetics of the RyR response induced by physiologically relevant, brief (<1-ms) Ca[sup 2+] stimuli. Instead, the changes in activation rate observed with sustained stimuli were translated into a drastic reduction in the probability of responses. Luminal Ca[sup 2+] did not affect the peak open probability or the probability of responses to brief Ca[sup 2+] signals; however, it slowed the transition to steady state and increased the steady-state open probability of the channel. Our results indicate that Mg[sup 2+] is a critical physiological determinant of the dynamic behavior of the RyR channel, which is expected to profoundly influence the fidelity of coupling between L-type Ca[sup 2+] channels and RyRs in heart cells. [ABSTRACT FROM AUTHOR]