Figure 2. Consequences of stimulatory action of MeHg on TRPs in sensory afferents.

Although MeHg blocks current carried through VGCCs (1), its ability to stimulate current through specific TRPC isoforms suggests these channels contribute to MeHg-induced Ca²⁺_i dysregulation (1). At the peripheral terminal and soma, elevations in [Ca²⁺]_i (2) may result in a lowered threshold for channel activation and, thus, hyperexcitability of the DRG (3). At the central terminal, MeHg-induced Ca²⁺ release from internal stores (4) may further add to [Ca²⁺]_i elevations mediated by TRPs (5). Such increases in [Ca²⁺]_i at the presynaptic terminal results in greater release of neurotransmitter (6) and, in turn, activation of postsynaptic receptors (7). MeHg-induced [Ca²⁺]_i dysregulation may ultimately lead to neuronal death. It is unclear whether dorsal horn neurons are affected secondarily through elevated [Ca²⁺]_i or through loss of synaptic input from the degenerating primary afferent.