Agrin Converts Electrical Coupling to Chemical Coupling

Science's STKE  17 May 2005:
Vol. 2005, Issue 284, pp. tw189
DOI: 10.1126/stke.2842005tw189

Agrin is a proteoglycan secreted by nerves that is well known for its role in organizing the postsynaptic regions of the neuromuscular junction (NMJ). However, agrin is not limited to nerves that innervate muscle and is a widely expressed protein, suggesting additional roles in synaptic organization in the central and peripheral nervous systems. Martin et al. provide evidence that agrin stimulates the switch from electrical coupling of cells to synaptic transmission in the adrenal gland. The abundance of the active form of agrin (Z+-agrin) increased during postnatal development of the adrenal gland and in adults was preferentially localized at cholinergic synaptic contacts. The amplitude, but not the frequency, of spontaneous excitatory postsynaptic currents (sEPSCs) in the neonatal adrenal gland, but not the adult gland, was increased by application of Z+-agrin. The effect appeared to be postsynaptic, based on an increase in the amplitude of the current evoked by application of nicotine (a ligand of acetylcholine receptors, nAChR). In neonatal adrenal gland, pharmacological inhibition of α3-type nAChR completely blocked sEPSCs; however, application of Z+-agrin resulted in sEPSCs that could only be blocked by inhibition of both α3 and α7 nAChR, as it does in the adult adrenal gland. In the neonatal adrenal gland, decay of the sEPSC was fitted by two exponentials and appeared to result in part from synaptic coupling and in part from gap junction-mediated coupling. Application of agrin or pharmacological inhibition of gap junctions converted this to a decay with a single time constant like that observed in adult gland. Within minutes, application of agrin decreased the percentage of electrically coupled cells in the neonatal adrenal gland (based on measurements of intercellular Lucifer yellow diffusion and intercellular macroscopic junctional currents), and within 1 hour, synaptic transmission was increased (based on increased sEPSC amplitude). The conversion of electrically coupled cells to synaptic transmission was blocked by pharmacological inhibition of Src, which is also implicated downstream of muscle-specific kinase (MuSK) in NMJ organization. MuSK was also detected in the neonatal and adult chromaffin gland. Thus, agrin appears to have a role in regulating the developmental switch from electrical coupling to chemical coupling in the adrenal gland.

A. O. Martin, G. Alonso, N. C. Guérineau, Agrin mediates a rapid switch from electrical coupling to chemical neurotransmission during synaptogenesis. J. Cell. Biol. 169, 503-514 (2005). [Abstract] [Full Text]