Primary afferent neurons are functionally heterogeneous. To determine whether this functional heterogeneity reflects, in part, heterogeneity in the regulation of the concentration of intracellular Ca(2+) ([Ca(2+)](i)), the magnitude and decay of evoked Ca(2+) transients were assessed in subpopulations of dorsal root ganglion (DRG) neurons with voltage clamp and fura-2 ratiometric imaging. To determine whether differences in evoked Ca(2+) transients among subpopulations of DRG neurons reflected differences in the contribution of Ca(2+) regulatory mechanisms, pharmacological techniques were employed to assess the contribution of influx, efflux, release and uptake pathways. Subpopulations of DRG neurons were defined by cell body size, binding of the plant lectin IB(4) and responsiveness to the algogenic compound capsaicin (CAP). Ca(2+) transients were evoked with 30 mm K(+) or voltage steps to 0 mV. There were marked differences between subpopulations of neurons with respect to both the magnitude and decay of the Ca(2+) transient, with the largest and most slowly decaying Ca(2+) transients in small-diameter, IB(4)-positive, CAP-responsive neurons. The smallest and most rapidly decaying transients were in large-diameter, IB(4)-negative and CAP-unresponsive DRG neurons. These differences were not due to a differential distribution of voltage-gated Ca(2+) currents. However, these differences did appear to reflect a differential contribution of other influx, efflux, release and uptake mechanisms between subpopulations of neurons. These results suggest that electrical activity in subpopulations of DRG neurons will have a differential influence on Ca(2+)-regulated phenomena such as spike adaptation, transmitter release and gene transcription. Significantly more activity should be required in large-diameter non-nociceptive afferents than in small-diameter nociceptive afferents to have a comparable influence on these processes.