Structure mirroring function: What's the 'matter' with the funny current?

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Biophysics

Background:

• The 'funny' (If) current is crucial for cardiac pacemaker activity and heart rate regulation.
• Previous models of pacemaking were based on a 'fake' K+ current (IK2), later identified as If.
• A similar current (Ih) regulates neuronal excitability.

Purpose of the Study:

• To compare the functional properties of the If current with the structure of the HCN4 protein.
• To determine if the structural features of HCN4 explain the unique characteristics of the If current.

Main Methods:

• Review of experimental data on If current properties (permeability, conductance, activation).
• Analysis of HCN4 channel structure using cryogenic electron microscopy.
• Comparison of functional data with structural insights.

Main Results:

• If current exhibits mixed Na+/K+ permeability and low single-channel conductance.
• Voltage and cyclic nucleotides (cAMP) dually activate If current, with cAMP binding directly to channels.
• HCN4 channel structure precisely explains these peculiar functional characteristics.

Conclusions:

• The unique functional properties of the If current are elegantly mirrored by the structural features of the HCN4 protein.
• Structural insights validate and explain the original interpretations of If current behavior.
• This provides a molecular basis for understanding cardiac rhythmicity and autonomic control.