Module 7 - Ion channels part 2 (P-loop channels, intro to ion selectivity) - 1

P-loop Channels Overview

  • P-loop channels are integral membrane proteins with significant evolutionary origins in bacteria.

Key Types of P-loop Channels

  1. Nav Channels (Voltage-gated Sodium Channels)

    • Conduct inward Na+ currents.

    • Depolarize the membrane potential (Vm) during the rising phase of action potentials.

  2. Kv Channels (Voltage-gated Potassium Channels)

    • Activated after Nav channels.

    • Conduct outward K+ currents, repolarizing the membrane potential.

Evolutionary Significance

  • Both types derive from ancient bacterial channels.

  • P-loop channels are critical in various physiological processes across organisms.

Emergence of P-loop Channels

  • P-loop channels originated billions of years ago from an initial prototype: Inward Rectifying Potassium (KIR) Channels.

  • Structure includes:

    • 2 Transmembrane Helices (TMHs) separated by an extracellular P-loop.

    • Tetrameric formation (4 subunits required to form a complete channel).

Ion Selectivity

  • Key amino acids within the P-loops define ion selectivity (specifically for K+ ions).

  • This forms the ion selectivity filter essential for channel function.

Evolution from KIR Channels

  1. Tandem Duplication of KIR Genes

    • Gave rise to 2-pore K+ leak channels (K2P channels).

    • Require only 2 proteins for channel function.

    • Critical for maintaining resting membrane potential (RMP).

    • Found exclusively in eukaryotes.

Functional Characteristics

  • K2P channels, while termed 'leak' channels, exhibit:

    • Gating and enhanced current flow due to stimuli such as pH, membrane stretch, and temperature.

Ionotropic Glutamate Receptors

  • Formed from the inversion across the membrane and the addition of a transmembrane helix.

  • Include AMPA, NMDA, and Kainate receptors, crucial for excitatory synaptic transmission (glutamatergic synapses).

  • Retain tetrameric structure and are ancient proteins originally from bacterial systems.

Voltage-Gated Channels

  • Emerged through fusion with a separately evolved bacterial protein (voltage sensor S1-S4). The S1-S4 sensors were fused with the KIR channels

  • Types include Kv channels, Ca2+-sensitive SK channels, and hyperpolarization-activated channels (HCN).

  • Some channels lost K+ selectivity, conducting Na+ and/or Ca2+ instead, crucial for sensory biology.

Voltage Sensor Domain (VSD)

  • Originated as a separate ion channel.

  • Two human genes (TPTE and TPTE2) conduct voltage-sensitive currents regulated by pH.

  • Mutations in VSD can create leak cation currents harmful to cells (example: Arginine→Histidine mutation in Nav1.4).

BK Channels

  • Evolved with an addition of a transmembrane helix at the N-terminus of Kv/SK/TRP channels.

  • SK channels refer to small conductance calcium-activated potassium channels, which are ion channels that open in response to increases in intracellular calcium levels.

  • TRP channels stand for transient receptor potential channels, a group of ion channels that are involved in various sensory modalities such as temperature and pain sensation.

  • Their gating is influenced by rises in cytoplasmic Ca2+ levels.

Two Pore Channels (TPC)

  • Resulted from a tandem duplication of Kv-like channels.

  • Dimeric structure; cationic (Ca2+, Na+).

  • Involved in calcium release from endo-lysosomes into the cytoplasm.

4-Domain Channels

  • Formed through tandem duplication of TPC-like channels:

    • Include Voltage-gated Na+ channels (Nav, cell depolarization during action potential) and Ca2+ channels (Cav, synaptic transmission, muscle contraction, gene expression).

  • NALCN is a Na+ leak channel that helps maintain RMP in neurons, crucial for neuronal function.

  • Yeast Ca2+ channel 1 is found in yeast and homologous with NALCN

Clinical Implications of Mutations

  • Mutations in the pore region are linked to congenital contractures, hypotonia, and developmental delays (CLIFAHDD).

  • Voltage sensor mutations result in infantile hypotonia and associated neurological effects (IHPRF1).