6-Regulation of GI Function Nerves & Smooth Muscle

Smooth muscle

Small, unstriated, no sarcomeres, dense bodies, no troponin (uses calmodulin), caveolae instead of T-tubules

Skeletal muscle

Large, striated, sarcomeres, troponin for Ca²⁺ binding, T-tubules present

Single-unit smooth muscle

Many gap junctions, pacemaker activity, coordinated contraction (e.g., GI tract, uterus, bladder)

Multi-unit smooth muscle

Little to no gap junctions, independent contraction via neurogenic stimulation (e.g., iris, vas deferens)

Dysfunction in single-unit smooth muscle

Dysfunction in pacemaker cells (Interstitial Cells of Cajal) can lead to gastroparesis, Hirschsprung's disease, or slow transit constipation

Impaired autonomic innervation in multi-unit smooth muscle

Can cause pupillary dysfunction, erectile dysfunction

Interstitial Cells of Cajal (ICCs)

Act as pacemakers generating slow-wave potentials in the GI tract

Slow-wave potentials

Cyclical depolarization & repolarization in GI smooth muscle

Action potentials

If threshold reached, triggers contraction via voltage-gated Ca²⁺ channels

Slow-wave potential

Graded oscillations in membrane potential

Calcium sources for smooth muscle contraction

1. Voltage-gated Ca²⁺ channels (extracellular source), 2. Sarcoplasmic reticulum (SR) Ca²⁺ release via RyR & IP₃R, 3. Store-operated Ca²⁺ channels (linked to SR Ca²⁺ depletion)

Role of Ca²⁺ in smooth muscle contraction

Ca²⁺ binds calmodulin, activating Myosin Light Chain Kinase (MLCK), which phosphorylates myosin light chains, allowing actin-myosin binding

Myosin Light Chain Phosphatase (MLCP)

Dephosphorylates myosin, leading to smooth muscle relaxation

Mechanisms of Ca²⁺ removal for relaxation

1. SERCA (SR Ca²⁺ ATPase) → Pumps Ca²⁺ back into SR, 2. PMCA (Plasma Membrane Ca²⁺ ATPase) → Pumps Ca²⁺ out of the cell, 3. Na⁺/Ca²⁺ Exchanger (NCX) → Uses Na⁺ gradient to extrude Ca²⁺

Na⁺/Ca²⁺ Exchanger (NCX)

Uses Na⁺ gradient to extrude Ca²⁺

Pharmacomechanical Coupling

Contraction triggered by chemical signals (hormones, NTs, drugs) via GPCRs, independent of voltage-gated Ca²⁺ channels

Latch State

Sustains tension with minimal ATP use; Myosin remains bound to actin longer, allowing prolonged contraction (e.g., GI sphincters)

Myenteric (Auerbach's) Plexus

Controls motility

Submucosal (Meissner's) Plexus

Controls secretion & blood flow

Autonomous smooth muscle activity

ICC pacemakers

Intrinsic nerve plexuses

ENS (local control)

Extrinsic autonomic control

ANS (sympathetic & parasympathetic)

Hormonal & paracrine regulation

Includes Gastrin, CCK, Secretin, etc.

Parasympathetic regulation of GI function

Vagus nerve (CN X) → upper GI; Pelvic nerves → distal colon, rectum; ACh release → ↑ motility, ↑ secretions

Sympathetic regulation of GI function

Preganglionic cholinergic, postganglionic adrenergic fibers; NE release → ↓ motility, ↓ secretions, ↑ sphincter tone

ACh & Substance P

Excitatory (↑ contraction, motility)

NO & VIP

Inhibitory (↓ contraction, ↑ relaxation)

Mechanoreceptors

Detect distension

Chemoreceptors

Detect pH, nutrients

Osmoreceptors

Detect luminal osmolarity

Short GI reflexes

Entirely within the ENS (e.g., peristalsis, secretion)

Long GI reflexes

Involve CNS modulation via vagus nerve

Hirschsprung's Disease

Absence of ganglion cells → Chronic constipation, megacolon

Achalasia

Dysphagia, food retention, esophageal dilation due to impaired LES relaxation from ENS dysfunction

Gastroparesis

Delayed gastric emptying associated with ICC dysfunction

Opioids effect on GI smooth muscle

Bind µ-opioid receptors → inhibit ACh release → ↓ peristalsis → constipation

Botulinum toxin mechanism

Blocks ACh release at neuromuscular junctions → relaxes smooth muscle; Used to treat achalasia, sphincter spasms