Molecular handoffs in nitrergic neurotransmission

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Postsynaptic density (PSD) proteins are largely immobile, with mobile scaffolding proteins beneath them.
• Shank proteins are positioned in the cytosolic face of PSDs, interacting with the actin cytoskeleton.
• PSD95 is found in prejunctional nerve terminals of nitrergic neurons in the gastrointestinal tract.

Purpose of the Study:

• To propose a hypothesis on the role of shank proteins in the transport and docking of neuronal nitric oxide synthase (nNOS).
• To explore the function of shank as an exchange hub for signaling proteins at the synapse.
• To investigate the potential link between shank deficiency, enteric nitrergic transmission, and gastrointestinal disorders like cyclical vomiting.

Main Methods:

• Review of existing literature on PSD proteins, shank, nNOS, and motor proteins.
• Hypothetical model proposed for nNOS transport and membrane docking involving shank.
• Analysis of shank knockout mouse models and human genetic data (Phelan-McDermid syndrome).

Main Results:

• Shank proteins may facilitate the exchange of dynein light chain LC8-nNOS with acto-myosin Va.
• Shank potentially aids in the transposition of nNOS for binding with palmitoyl-PSD95 at the nerve terminal membrane.
• Shank deficiency is linked to autism spectrum disorders and may cause junctionopathy in enteric nitrergic nerve terminals, potentially leading to cyclical vomiting.

Conclusions:

• Shank proteins play a critical role in the trafficking and synaptic integration of nNOS.
• The proposed mechanism highlights shank's importance in enteric nitrergic neuromuscular transmission.
• Shank deficit is a plausible cause for junctionopathy underlying cyclical vomiting in Phelan-McDermid syndrome.